Neoadjuvant Combination Immunotherapy for Colorectal Cancer: Clinical and Molecular Predictors of Pathological Complete Response and Safety Assessment

Neoadjuvant Combination Immunotherapy for Colorectal Cancer: Clinical and Molecular Predictors of Pathological Complete Response and Safety Assessment | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Neoadjuvant Combination Immunotherapy for Colorectal Cancer: Clinical and Molecular Predictors of Pathological Complete Response and Safety Assessment Yuegang Li, Meng Zhuang, Shiwen Mei, Gang Hu, Wei Zhao, Wenlong Qiu, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4001747/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Purpose To identify the clinical and molecular factors that effectively predict pathological complete response (pCR) and assess the safety of patients receiving neoadjuvant combination immunotherapy. Materials and Methods This retrospective study evaluated 81 patients with colorectal cancer (CRC) at a Chinese tertiary center between 2015 and 2023. The cohort included 24 patients with deficient mismatch repair (dMMR) tumors and 57 patients with proficient mismatch repair (pMMR) tumors. Patients were treated with a neoadjuvant combination of immunotherapy and surgery. Results We enrolled 81 patients who were divided into pCR (39.3%) and non-pCR (79.7%) groups. The factors significantly associated with a higher pCR rate after neoadjuvant combination immunotherapy were younger age, low carcinoembryonic antigen (CEA) level, high tumor mutational burden (TMB) level before treatment, clinical stage III, absence of lymph node metastasis before treatment, MSI-H level, dMMR, and pole status mutation. Preoperative combined chemotherapy and targeted therapy also influenced the pCR rate. Neoadjuvant combination immunotherapy showed an overall adverse event (AE) rate of 29.6%, with none of grades 3–4. Surgery-related adverse reactions (srAEs) were also absent for grades 3–4, and 14 of the 81 patients experienced grade 1–2 AEs. Conclusion Neoadjuvant combination immunotherapy resulted in a favorable pCR rate in patients with CRC. Young age, pretreatment CEA level, TMB level, clinical stage, lymph node metastasis, MSI, MMR, and pole status can be used as indicators of the efficacy of neoadjuvant combination immunotherapy. The incidence of AEs from neoadjuvant combination immunotherapy and surgery was low, indicating that this regimen is safe and feasible. colorectal neoplasms pathological complete response neoadjuvant combination immunotherapy surgery safety Figures Figure 1 1 Introduction Immunotherapy has become a popular research topic for patients with colorectal cancer (CRC). The results of the KEYNOTE-016 study, reported at the 2015 ASCO Annual Meeting, led to the adoption of immunotherapy for CRC [ 1 ]. The NICHE-1 was the first to apply immunotherapy to colon cancer neoadjuvant therapy, and the results showed that short-term preoperative immunotherapy was safe and feasible [ 2 ]. The NICHE-2 study enrolled 120 patients with locally advanced dMMR colon cancer and the results showed a pCR rate of 67% (72/107) [ 3 ]. Patients with dMMR or microsatellite instability-high (MSI-H) belong to the “hot tumor” population that is sensitive to immunotherapy. However, they account for only 10 ~ 15% of CRC, and a larger proportion of patients with pMMR or microsatellite stability (MSS) belong to the “cold tumor” population that is insensitive to immunotherapy [ 4 ]. Some patients with pMMR or MSS respond to neoadjuvant immunotherapy combined with other treatment methods, such as radiotherapy, chemotherapy, and targeted therapy [ 5 – 8 ]. However, there is no consensus on how to identify effective predictors of pCR, and the safety of neoadjuvant combination immunotherapy has seldom been reported. Therefore, we conducted a retrospective exploratory analysis to evaluate the effectiveness and safety of neoadjuvant combination immunotherapy and to identify the clinical and molecular predictors of pCR. 2 Materials and Methods 21. Patients This study retrospectively evaluated a cohort of patients with CRC who received immune checkpoint inhibitors (ICI). We extracted all cases from February 2015 to September 2023 from a prospectively collected institutional database and tumor registry. The following inclusion criteria were met by the participants: (1) colonoscopy-confirmed adenocarcinoma; (2) Preoperative treatment, including ICI; (3) complete primary lesion surgery; and (4) pretreatment imaging data and MMR status by immunohistochemistry (IHC). We excluded patients who (1) received other types of antitumor or experimental treatments, (2) previously received ICI treatment, or (3) had other malignant tumors in the past five years. This study was approved by the Ethics Committee of the Cancer Hospital of the Chinese Academy of Medical Sciences (approval number 23/535–4278). Written informed consent was obtained from all participants. 2.2 Treatment procedure The treatment plan used ICI (manufacturer unlimited; dosage according to the opinion of the attending physician) in combination with other treatments, including chemotherapy, radiotherapy, and targeted therapy. Following the completion of neoadjuvant combination immunotherapy, patients were restaged using chest, abdominal, and pelvic CT scans. Restaging with MRI, flexible endoscopy, and/or EUS was used to evaluate lesion regression. All the patients underwent laparoscopic or open surgery. For patients with distant metastases before treatment, if residual metastases were considered after treatment, a multidisciplinary consultation was conducted to determine the need for combined metastatic resection. 2.3 Data collection The data included basic patient information, such as sex, age, body mass index (BMI), family history, tumor location, preoperative imaging data, colonoscopy pathology data, carcinoembryonic antigen (CEA) level, hemoglobin (Hb) level, and neutrophil-to-lymphocyte ratio (NLR). Additionally, genetic testing of tumor tissues or blood samples, including MMR status, MSI status, and mutations in the KRAS, NRAS, BRAF, tp53, pole, and PIK3CA genes, was performed before treatment, if possible. Finally, the time intervals between the different treatment stages and postoperative pathological results, such as pathological tumor-node-metastasis (pTNM) staging and tumor regression grade (TRG), were analyzed. 2.4 Efficacy and safety evaluation The Dowrak/Rödel TRG system [ 9 ] has four levels: (1) TRG-0 is no response; (2) TRG-1 is less than 25% fibrosis in the tumor; (3) TRG2 is 25%-50% fibrosis in the tumor; (3) TRG-3 is more than 50% fibrosis in the tumor; and (3) TRG-4 is complete remission. Consequently, pCR was defined as tumor regression induced by neoadjuvant combination immunotherapy without residual cancer or positive lymph nodes (pCR = TRG-4). AEs were assessed using the Common Adverse Event Evaluation Criteria (CTCAE) version 5.0, published by the US Department of Health and Human Services [ 10 ]. Immunity-related adverse events (irAEs) were evaluated according to literature standards [ 11 ]. 2.5 Statistical analysis Statistical analyses were performed using the IBM SPSS Statistics version 26 (IBM, Armonk, NY, USA). Categorical variables were compared using Pearson’s chi-square and Fisher’s exact tests, whereas continuous variables were analyzed using the Kruskal–Wallis H-test. Statistical significance was set at p < 0.05. 3 Results 3.1 Patient characteristics This study included 81 patients with CRC who met the inclusion criteria between February 2015 and September 2023. A total of 33 patients (40.7%) achieved pCR, whereas 48 (59.3%) did not. A flowchart of the study is shown in Figure 1 . The average age was 54.6±12.3 years, with a median BMI of 23.8 kg/m 2 (IQR 21.5-26.0), and a median CEA level of 4.0 ng/mL (IQR (1.8-17.2)) before treatment. Of the 81 patients, 44 were male (54.3%) and 37 were female (45.7%). Regarding the primary tumor site, 43 patients had rectal cancer (53.1%), 15 had sigmoid colon cancer (18.5%), and 23 had ascending colon cancer (28.4%). According to the clinical stage before treatment, 11 (13.6 %), 49 (60.5 %), and 21 (25.9 %) patients had stages II, III, and IV disease, respectively. According to MMR status, there were 24 cases of dMMR (29.6%) and 57 cases of pMMR (70.4%). 3.2 Clinical and molecular predictors of pCR Patients with younger age (50 vs. 58 years; p = 0.003), low CEA level (2.1 vs 8.6; p < 0.001), high tumor mutational burden (TMB) level (68 vs. 5; p < 0.001) before treatment, clinical stage III (69.7% vs. 54.2%; p < 0.001), and no lymph node metastasis before treatment (24.2% vs. 6.3%; p = 0.049) were more likely to achieve pCR after receiving neoadjuvant combination immunotherapy. There were no significant differences in sex, BMI, family history, primary tumor site, NLR, Hb level, lesion length, or T stage before treatment between the pCR and non-pCR groups (p > 0.05) ( Table 1 ). Combining the pathological, IHC, and genetic testing results of some patients before treatment, we found that patients with MSI-H (42.4% vs. 12.5%, p = 0.003), dMMR (48.5% vs. 18.7%, p = 0.002), and combined pole gene mutations (21.2% vs. 2.1%, p = 0.008) were more likely to achieve a pCR (p < 0.05). However, we did not find any statistically significant differences in tumor differentiation, Lynch syndrome, KRAS, NRAS, BRAF, TP53, or PIK3CA mutations between the pCR and non-pCR groups ( Table 2 ). Among 81 patients, the median time from diagnosis to the start of their first treatment was 28 days (IQR: 14-45.5). From the start of neoadjuvant therapy to its completion, the median time was 100 days (IQR: 71.5-145.5). Following neoadjuvant therapy, the median interval was 46 days (IQR: 34.5-63) until surgery. Notably, there were no significant differences in the time intervals between the pCR and non-pCR groups ( Table 3 ). Among these cases, 62 used PD-1 inhibitors, nine used PD-L1 inhibitors, and 10 used a combination of PD-1 and CTLA-4 inhibitors. Primary preoperative chemotherapy regimens included CAPOX (n = 71) and FOLFOX (n = 4). Additionally, 22 patients with rectal cancer underwent synchronous preoperative radiotherapy and chemotherapy. The chemotherapy regimen was primarily capecitabine, with 13 patients undergoing short-course radiotherapy (SCRT) and nine receiving long-course radiotherapy (LCRT). Furthermore, preoperative combination chemotherapy (p = 0.021) and targeted therapy (p = 0.01) affected postoperative pCR rates ( Table 3 ). 3.3 Postoperative pathological outcomes Based on MMR status, the 81 patients were categorized into two groups: dMMR (n = 24) and pMMR (n = 57). Remarkably, all patients achieved an objective response rate (ORR). In the dMMR group, a significantly higher proportion of patients achieved pCR than in the pMMR group (66.7% vs. 29.8%, p < 0.05). Additionally, the dMMR group exhibited a higher rate of postoperative N0 status than the pMMR group (83.3% vs. 61.4%, p = 0.20). Furthermore, the dMMR group had a lower incidence of vascular (12.5% vs. 22.8%, p = 0.43) and perineural invasion (12.5% vs. 29.8%, p = 0.099) than the pMMR group ( Table 4 ). 3.4 Neoadjuvant therapy- and surgical-related AEs The overall AE rate associated with neoadjuvant chemoradiotherapy (nCRT) and neoadjuvant chemotherapy (NAC) was 70.3%. Among these reactions, 3-4 grade events account for 16.0%. In contrast, the total AE rate of neoadjuvant ICIs was 29.6%, with no observed 3-4 grade adverse reactions observed. The main irAEs were fever (4.9%), fatigue (4.9%), rash or pruritus (7.4%), and diarrhea (8.6%). In contrast, the AEs associated with nCRT/NAC predominantly included hand-and-foot syndrome (19.8%), nausea (17.3%), and vomiting (12.3%). Remarkably, after neoadjuvant combination immunotherapy and surgery, no 3-4 grade srAEs were observed. Instead, 1-2 grade AEs included blood loss >100 mL in seven cases, anastomotic leakage in two cases, ileus in one case, chylous fistula in one case, incisional hernia in one case, a perineal incision in three cases, and stoma infection in one case ( Table 5 ). 4 Discussion In this single-center retrospective study, all patients received immunotherapy before surgery. After surgery, more than 40% of patients achieved pCR, with 66.7% and 29.8% of patients with dMMR and pMMR colorectal cancer achieving pCR, respectively. Additionally, this study suggests that the factors predicting pCR include younger age, lower CEA levels before treatment, clinical stage III, negative clinical lymph nodes, and molecular pathology including MSI-H, dMMR, pole gene mutations, and higher TMB levels. The traditional neoadjuvant treatment methods for colon cancer include chemotherapy, radiotherapy, targeted therapy, and combination therapy. Currently, neoadjuvant treatment for rectal cancer is based on a combination of radiotherapy and chemotherapy [ 12 – 14 ]. The ORR of colorectal cancer with monotherapy is 40%, and the pCR rate is 5% [ 15 ]. The pCR rate of combined radiotherapy and chemotherapy is 10–15% [ 16 ]. Garcia-Aguilar et al. found that TNT therapy achieved pCR in 38% of rectal cancer patients [ 17 ]. Our research found that compared to traditional treatment methods, neoadjuvant combination immunotherapy can increase the rate of complete pathological remission after surgery, with more than 40% of patients achieving pCR, including 39.4 (13/43) of patients with rectal cancer who achieved pCR. This shows that neoadjuvant combination immunotherapy can improve the rate of pCR compared with traditional treatment methods. In addition, a Voltage study [ 6 ] explored a new neoadjuvant immunotherapy with nivolumab after long-distance synchronous radiotherapy and chemotherapy for locally advanced rectal cancer. The pCR rate in the dMMR group was 60%, which is consistent with our results. Among 24 patients with dMMR, 16 (66.7%) achieved pCR. Lin et al. [ 18 ] reported that the pCR rate in 26 patients with pMMR rectal cancer receiving short-term radiotherapy combined with camrelizumab and CapeOx was 46.2%. In our study, 29.8% (17/57) of patients achieved complete pathological remission. Because our study included both colon and rectal cancer cases and there were mixed factors, such as treatment plan, treatment cycle, small data volume, and tumor staging, the optimal treatment plan for combination therapy cannot be determined at present. In patients with pMMR or MSS CRC, the optimization of new neoadjuvant immunotherapy regimens and the identification of effective biomarkers to predict therapeutic efficacy are important research topics. Currently, a few potential markers such as POLE or POLD1 gene mutations, TMB, immune score, PD-L1 expression, CD8 + /Treg ratio, and intestinal flora [ 5 , 6 , 19 , 20 ]. In a study of patients with MSI-H mCRC receiving PD-1 and PD-L1 treatment, all 13 patients with high TMB achieved objective remission, whereas six of nine patients with low TMB experienced tumor progression [ 21 ]. Therefore, TMB is an effective biomarker; however, there is controversy over its optimal cutoff value when applied as a marker for predicting the efficacy of immunotherapy. Because different studies are based on different detection platforms and panels, they have different cutoff values. Determining the optimal cutoff value for TMB is another direction that should be explored in future studies. Colorectal tumors with POLE or POLD1 gene mutations are of the MSS type and can benefit from PD-1 monoclonal antibody treatment; however, this type of mutation accounts for only 1% of colorectal cancer cases [ 22 ]. In a retrospective study using CEA levels to predict pCR, lower CEA levels were associated with pCR. Additionally, CEA levels before and after neoadjuvant therapy can be used to predict pCR [ 23 , 24 ]. Clinical staging is related to patient risk stratification, which distinguishes patient risk by analyzing patient images and pathological results combined with the T stage, N stage, and other factors. However, the specific application of these indicators to predict the efficacy of neoadjuvant therapy and to define the weight of each indicator requires further exploration. Among the 81 patients included in the study, AEs such as fever (4.9%), fatigue (4.9%), rash or pruritus (7.4%), and diarrhea (8.6%) were observed; however, there were no treatment-related deaths or severe adverse reactions. In the KEYNOTE-177 study [ 25 ], the pembrolizumab group had a 31% incidence of immune- and infusion-related adverse reactions, of which 9% were grade 3 or 4, with colonic inflammation and hepatitis being the most common. The adverse reaction outcomes of this study were similar to those of the KEYNOTE-177 study; however, no grade 3–4 AEs were observed, indicating that neoadjuvant immunotherapy for colorectal cancer is safe. Grade 1–2 AEs caused by neoCRT/NAC included hand-and-foot syndrome (19.8%), nausea (17.3%), and vomiting (12.3%). In the NICHE study (2), 20% of the 40 patients who underwent colon resection surgery had grade III surgical complications, and the incidence of anastomotic leakage was as high as 10%, including five cases of abdominal (or incision) infection, one case of intestinal obstruction, one case of pneumonia, and one case of small intestinal injury; the high incidence of anastomotic leakage may be related to the combined use of PD-1 and CTLA-4. In this study, there were only two cases of anastomotic leakage after CRC surgery, both of which improved with conservative treatment. Seven patients had intraoperative bleeding of > 100 mL, one had ileus, one had a chylous fistula, one had an incisional hernia, three had a perineal incision, and one had a stoma infection; however, there were no perioperative deaths. This single-center, retrospective study has several limitations. First, the study only included patients with CRC who underwent surgical treatment and excluded patients who achieved complete clinical remission after neoadjuvant therapy, those whose disease progressed, and those who could not undergo surgery, which may have caused a selection bias. Second, the study included patients with colon and rectal cancers, including those with advanced CRC, and there were differences in the preoperative medication plans and cycles, which may have affected the statistical results. Finally, the sample size was relatively small. Further multicenter prospective studies with larger sample sizes are warranted. 5 Conclusion Neoadjuvant combination immunotherapy has a favorable pCR rate in patients with CRC. Young age, pretreatment CEA level, TMB level, clinical stage, lymph node metastasis, MSI, MMR, and pole status can be used as indicators of the efficacy of neoadjuvant combination immunotherapy. No severe AEs were observed in the patients in this group, indicating that neoadjuvant combination immunotherapy is safe and reliable. Declarations Conflict of Interest We declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Funding This study was supported by grants from the National Natural Science Foundation of China (no. 82072732) and the Beijing Natural Science Foundation (L222054, 4232058). Author Contribution All authors contributed to the study conception and design. Drafting the work and/or revising it critically: Yuegang Li, Meng Zhuang, Shiwen Mei, Wei Zhao and Wenlong Qiu. Final approval of the version to be published: Xishan Wang, and Jianqiang Tang. All authors contributed to the article and approved the submitted version. Data Availability Statement The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation. References Lenz HJ, Van Cutsem E, Luisa Limon M (2022) First-line nivolumab plus low-dose ipilimumab for microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer: The Phase II CheckMate 142 study. J Clin Oncol. https://doi.org/10.1200/JCO.21.01015 . .40:161 – 70 Chalabi M, Fanchi LF, Dijkstra KK (2020) Neoadjuvant immunotherapy leads to pathological responses in MMR-proficient and MMR-deficient early-stage colon cancers. 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Characteristics Total (n=81) pCR (n=33) Non-pCR (n=48) P value Age, years 54.6±12.3 49.5±13.5 58.2±19.0 0.003 Sex, male 44(54.3) 19(57.6) 25(52,1) 0.63 BMI, kg/m 2 23.8(21.5-26.0) 23.6(21.5-26.3) 24.1(21.1-26.2) 1.00 Family history of cancer Yes No 21(25.9) 60(74.1) 7(21.2) 26(78.8) 14(29.2) 34(70.8) 0.42 Primary tumor location Ascending colon Sigmoid colon Rectum 23(28.4) 15(18.5) 43(53.1) 13(39.4) 7(21.2) 13(39.4) 10(20.8) 8(16.7) 30(62.5) 0.10 Clinical TNM stage II III IV 11(13.6) 49(60.5) 21(25.9) 8(24.2) 23(69.7) 2(6.1) 3(6.2) 26(54.2) 19(39.6) ＜0.001 Clinical T-stage T3 T4 36(44.4) 45(55.6) 17(51.5) 16(48.5) 19(39.6) 29(69.4) 0.29 Clinical N-stage 0 1 2 11(13.6) 49(60.5) 21(25.9) 8(24.2) 19(57.6) 6(18.2) 3(6.3) 30(62.5) 15(31.3) 0.049 Length of lesion 4.8(4.15-5.95) 4.6(3.8-5.9) 4.9(4.23-6.05) 0.395 Hb, g/L 126.7±25.0 127.2±27.7 126.4±23.3 0.89 NLR 2.56(1.84-3.48) 2,73(2.15-3.64) 2.47(1.70-3.39) 0.19 CEA, ug/L 4.0(1.8-17.2) 2.1(1.4-14.7) 8.6(2.3-27.5) ＜0.001 TMB, mutation/Mb a 10.6(4.0-61.8) 68.0(25.0-188.3) 5.1(3.1-11.3) ＜0.001 Abbreviation: pCR, pathological complete response; BMI, Body mass index; TNM, Tumor Node Metastasis; Hb, Hemoglobin; NLR, Neutrophil-lymphocyte ratio; CEA, Carcinoembryonic antigen; TMB, Tumor mutational burden a 44 cases with TMB values detected were included in the analysis. Table 2. Pathologic Findings on pre-treatment biopsy Characteristics Total (n=81) pCR (n=33) Non-pCR(n=48) P value Histological appearance Well differentiated Moderately differentiated Poorly differentiated 2(2.5) 14(17.3) 65(80.2) 1(3.0) 5(15.2) 27(81.8) 1(2.1) 9(18.7) 38(79.2) 0.89 Lynch syndrome Yes No Unknown 5(6.2) 31(38.3) 45(55.6) 3(9.1) 13(39.4) 17(51.5) 2(4.2) 18(37.5) 28(58.3) 0.62 MSI status MSS MSI-High Not tested 38(46.9) 20(24.7) 23(28.4) 9(27.3) 14(42.4) 10(30.3) 29(60.4) 6(12.5) 13(27.1) 0.003 MMR status dMMR pMMR 24(29.6) 57(70.4) 16(48.5) 17(51.5) 8(16.7) 40(83.3) 0.002 Any mutation Yes No Unknown 48(59.3) 11(13.6) 22(27.2) 17(51.5) 5(15.2) 11(33.3) 31(64.6) 6(12.5) 11(22.9) 0.49 KRAS status Yes No Unknown 30(37.0) 29(35.8) 22(27.2) 10(30.3) 12(36.4) 11(33.3) 20(41.7) 17(35.4) 11(22.9) 0.48 NRAS status Yes No Unknown 5(6.2) 54(66.7) 22(27.2) 2(6.1) 20(60.6) 11(33.3) 3(6.3) 34(70.8) 11(22.9) 0.58 BRAF status Yes No Unknown 9(11.1) 50(61.7) 22(27.2) 2(6.1) 20(60.6) 11(33.3) 7(14.6) 30(62.5) 11(22.9) 0.36 TP53 mutation Yes No Unknown 23(28.4) 35(43.2) 23(28.4) 8(24.2) 14(42.4) 11(33.3) 15(31.2) 21(43.8) 12(25.0) 0.66 Pole status Yes No Unknown 8(9.9) 49(60.5) 24(29.6) 7(21.2) 15(45.5) 11(33.3) 1(2.1) 34(70.8) 13(27.1) 0.008 PIK3CA status Yes No Unknown 12(14.8) 47(58.0) 22(27.2) 5(15.2) 17(51.5) 11(33.3) 7(14.6) 30(62.5) 11(22.9) 0.55 Abbreviation: pCR, pathological complete response; MSI, microsatellite instability; MSS, microsatellite stable; MMR, mismatch repair; dMMR, Mismatch repair deficient; pMMR, Mismatch repair proficient Table 3. Neoadjuvant treatment characteristics Variable Total (n=81) pCR (n=33) Non-pCR(n=48) P value Days from diagnosis to initiation of any therapy 28(14-45.5) 35(16-52.5) 22(14-40) 0.13 Days from initiation of any therapy to completion of all therapy 100(71.5-145.5) 100(75.5-137.5) 100.5(69.25-153) 0.91 Days from completion of all therapy to surgery 46(34.5-63) 49(35-61.5) 44.5(33.25-63.5) 0.79 Neoadjuvant immunotherapy PD-1 inhibitor PD-L1 inhibitor PD-1/CTLA-4 inhibitors 62(76.5) 9(11.3) 10(12.3) 26(78.8) 2(6.1) 5(15.2) 36(75.0) 7(14.6) 5(10.4) 0.43 NAC Yes No 76(93.8) 5(6.2) 28(84.8) 5(15.2) 48(100) 0(0) 0.021 Initial NAC reduction/stop Yes No 15(20.0) 60(80.0) 7(25.9) 20(74.1) 8(16.7) 40(83.3) 0.34 Target therapy before surgery Yes No 28(34.6) 53(65.4) 6(18.2) 27(81.8) 22(45.8) 26(54.2) 0.01 nCRT Yes No 22(27.2) 59(72.8) 11(33.3) 22(66.7) 11(22.9) 37(77.1) 0.30 Type of nCRT LCRT SCRT 9(40.9) 13(59.1) 3(27.3) 8(72.7) 6(54.5) 5(45.5) 0.19 Abbreviation: pCR, pathological complete response; NAC, Neoadjuvant chemotherapy; nCRT, Neoadjuvant chemoradiotherapy; LCRT, Long-course chemoradiotherapy; SCRT, Short-course chemoradiotherapy Table 4. Pathological outcomes of 81 patients after surgery Characteristics dMMR (N=24) pMMR (N=57) P value ORR 24/24(100) 57/57(100) - Pathological response rate 24/24(100) 57/57(100) - pCR rate 16/24(66.7) 17/57(29.8) 0.002 TRG 1 2 3 4 3/24 (12.5) 1/24 (4.2) 4/24 (16.7) 16/24(66.7) 8/57(14.0) 23/57(40.4) 9/57(15.8) 17/57(29.8) 0.004 Pathological T stage ypT0 ypT1 ypT2 ypT3 ypT4 15/24(62.5) 1/24(4,2) 2/24(8.3) 2/24(8.3) 4/24(16.7) 17/57(29.8) 4/57(7.0) 8/57(14.0) 16/57(28.1) 12/57(21.1) 0.08 Pathological N stage ypN0 ypN1 ypN2 20/24(83.3) 2/24 (8.3) 2/24 (8.3) 35/57(61.4) 13/57(22.8) 9/57(15.8) 0.20 Pathological TNM stage 0 I II III IV 16/24(66.7) 2/24(8.3) 1/24(4.2) 2/24(8.3) 3/24(12.5) 17/57(29.8) 9/57(15.8) 7/57(12.3) 13/57(22.8) 11/57(19.8) 0.04 Vascular invasion 3(12,5) 13(22.8) 0.43 Perineural invasion 3(12.5) 17(29.8) 0.099 Abbreviation: ORR, Objective response rate; pCR, Pathological complete response; TRG, Tumor regression grade; TNM, Tumor Node Metastasis; dMMR, Mismatch repair deficient; pMMR, Mismatch repair proficient Table 5. Neoadjuvant therapy-related and surgical-related adverse events Adverse Events nCRT/NAC neoICIs Grade 1-2 Grade 3-4 Grade 1-2 Grade 3-4 Any 44(54.3) 13(16.0) 24(29.6) 0 Fever 0 0 4(4.9) 0 Fatigue 0 0 4(4.9) 0 Rash or pruritus 0 0 6(7.4) 0 Hand and foot syndrome 16(19.8) 1(1.2) 0 0 Nausea 14(17.3) 9(11.1) 0 0 Vomit 10(12.3) 2(2.5) 0 0 Abdominal pain 3(3.7) 0 1(1.2) 0 Diarrhea 1(1.2) 1(1.2) 7(8.6) 0 Bowel obstruction 2(2.5) 0 0 0 Anal pain 4(4.9) 0 0 0 Urinary tract pain 1(1.2) 0 0 0 Hyperthyroidism 0 0 2(2.5) 0 Hypothyroidism 0 0 1(1.2) 0 Aminotransferase increased 0 0 3(3.7) 0 Myelosuppression 8(9.9) 3(3.7) srAEs Grade1-2 Grade 3-4 Blood loss>100ml 7(8.6) 0 Anastomotic leakage a 2(2.9) 0 Ileus 1(1.2) 0 Chylous fistula 1(1.2) 0 Incisional hernia 1(1.2) 0 Perineal incision b 3(42.9) 0 Stoma infection c 1(26.3) 0 Abbreviation: NAC, Neoadjuvant chemotherapy; nCRT, Neoadjuvant chemoradiotherapy; neoICIs, Neoadjuvant immune checkpoint inhibitions; srAEs, Surgical-related adverse events a: 70 cases with anastomoses, b: 7 cases underwent Mile’s surgery, c: 38 cases with stoma Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4001747","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":276443356,"identity":"b822c3f1-e5f2-4a9a-b62d-892ef778057c","order_by":0,"name":"Yuegang Li","email":"","orcid":"","institution":"National Cancer Center, Chinese Academy of Medical Sciences and Peking Union Medical College","correspondingAuthor":false,"prefix":"","firstName":"Yuegang","middleName":"","lastName":"Li","suffix":""},{"id":276443357,"identity":"f7b288b7-955e-4a1c-8027-8fb93cfdfed4","order_by":1,"name":"Meng Zhuang","email":"","orcid":"","institution":"National Cancer Center, Chinese Academy of Medical Sciences and Peking Union Medical College","correspondingAuthor":false,"prefix":"","firstName":"Meng","middleName":"","lastName":"Zhuang","suffix":""},{"id":276443358,"identity":"31c979e4-aba3-4669-b4c6-208bab758665","order_by":2,"name":"Shiwen Mei","email":"","orcid":"","institution":"National Cancer Center, Chinese Academy of Medical Sciences and Peking Union Medical College","correspondingAuthor":false,"prefix":"","firstName":"Shiwen","middleName":"","lastName":"Mei","suffix":""},{"id":276443359,"identity":"230daace-24a1-4dc6-81d1-4a594658588b","order_by":3,"name":"Gang Hu","email":"","orcid":"","institution":"National Cancer Center, Chinese Academy of Medical Sciences and Peking Union Medical College","correspondingAuthor":false,"prefix":"","firstName":"Gang","middleName":"","lastName":"Hu","suffix":""},{"id":276443360,"identity":"e28186f4-2ca6-4d24-ba7d-4575b36cad2d","order_by":4,"name":"Wei Zhao","email":"","orcid":"","institution":"National Cancer Center, Chinese Academy of Medical Sciences and Peking Union Medical College","correspondingAuthor":false,"prefix":"","firstName":"Wei","middleName":"","lastName":"Zhao","suffix":""},{"id":276443361,"identity":"7bc0d126-a2ab-4e89-8733-1572dc8ab3f8","order_by":5,"name":"Wenlong Qiu","email":"","orcid":"","institution":"National Cancer Center, Chinese Academy of Medical Sciences and Peking Union Medical College","correspondingAuthor":false,"prefix":"","firstName":"Wenlong","middleName":"","lastName":"Qiu","suffix":""},{"id":276443362,"identity":"0145c243-05df-4445-a884-e95953ff1a4e","order_by":6,"name":"Xishan Wang","email":"","orcid":"","institution":"National Cancer Center, Chinese Academy of Medical Sciences and Peking Union Medical College","correspondingAuthor":false,"prefix":"","firstName":"Xishan","middleName":"","lastName":"Wang","suffix":""},{"id":276443363,"identity":"37a67acd-43d7-4007-9419-96a2a838b858","order_by":7,"name":"Jianqiang Tang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAyklEQVRIiWNgGAWjYDCCAyCCh0HOAMwzsCBSywEeBmMDBmaQFglitTAwJG4Aa2EgQgvf8eYHzB9krNO3s/cf3fCjQIKBv707Aa8WyTPHDIAOS8/d2XOY7WYP0GESZ85uwKvF4EYOyC+HczfcSGa7wQPUYiCRS5yWdAOglpt/SNGSANJymyhbwH45w5NuuOHMYbPbMgYSPAT9Agoxhsoea3mD443Pbr75YyPH396LXwsQsP9g7GGG83gIKYeCH8yE1YyCUTAKRsHIBQCCsUhIQ59vKQAAAABJRU5ErkJggg==","orcid":"","institution":"National Cancer Center, Chinese Academy of Medical Sciences and Peking Union Medical College","correspondingAuthor":true,"prefix":"","firstName":"Jianqiang","middleName":"","lastName":"Tang","suffix":""}],"badges":[],"createdAt":"2024-03-01 02:21:48","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4001747/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4001747/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":52186045,"identity":"fcd2bee3-5a34-4df8-9c09-3178c63b9045","added_by":"auto","created_at":"2024-03-07 18:25:12","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":39032,"visible":true,"origin":"","legend":"\u003cp\u003eFlowchart of patient selection\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-4001747/v1/8a0629b72b013ac2db57ac2d.png"},{"id":54830509,"identity":"0687619f-4e3b-498b-b602-293bc4f162df","added_by":"auto","created_at":"2024-04-17 11:02:43","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":316332,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4001747/v1/e52a1537-185d-4377-b234-1a53e8620dfe.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Neoadjuvant Combination Immunotherapy for Colorectal Cancer: Clinical and Molecular Predictors of Pathological Complete Response and Safety Assessment","fulltext":[{"header":"1 Introduction","content":"\u003cp\u003eImmunotherapy has become a popular research topic for patients with colorectal cancer (CRC). The results of the KEYNOTE-016 study, reported at the 2015 ASCO Annual Meeting, led to the adoption of immunotherapy for CRC [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. The NICHE-1 was the first to apply immunotherapy to colon cancer neoadjuvant therapy, and the results showed that short-term preoperative immunotherapy was safe and feasible [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. The NICHE-2 study enrolled 120 patients with locally advanced dMMR colon cancer and the results showed a pCR rate of 67% (72/107) [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Patients with dMMR or microsatellite instability-high (MSI-H) belong to the \u0026ldquo;hot tumor\u0026rdquo; population that is sensitive to immunotherapy. However, they account for only 10\u0026thinsp;~\u0026thinsp;15% of CRC, and a larger proportion of patients with pMMR or microsatellite stability (MSS) belong to the \u0026ldquo;cold tumor\u0026rdquo; population that is insensitive to immunotherapy [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Some patients with pMMR or MSS respond to neoadjuvant immunotherapy combined with other treatment methods, such as radiotherapy, chemotherapy, and targeted therapy [\u003cspan additionalcitationids=\"CR6 CR7\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. However, there is no consensus on how to identify effective predictors of pCR, and the safety of neoadjuvant combination immunotherapy has seldom been reported. Therefore, we conducted a retrospective exploratory analysis to evaluate the effectiveness and safety of neoadjuvant combination immunotherapy and to identify the clinical and molecular predictors of pCR.\u003c/p\u003e"},{"header":"2 Materials and Methods","content":"\u003cp\u003e21. Patients\u003c/p\u003e \u003cp\u003eThis study retrospectively evaluated a cohort of patients with CRC who received immune checkpoint inhibitors (ICI). We extracted all cases from February 2015 to September 2023 from a prospectively collected institutional database and tumor registry. The following inclusion criteria were met by the participants: (1) colonoscopy-confirmed adenocarcinoma; (2) Preoperative treatment, including ICI; (3) complete primary lesion surgery; and (4) pretreatment imaging data and MMR status by immunohistochemistry (IHC). We excluded patients who (1) received other types of antitumor or experimental treatments, (2) previously received ICI treatment, or (3) had other malignant tumors in the past five years. This study was approved by the Ethics Committee of the Cancer Hospital of the Chinese Academy of Medical Sciences (approval number 23/535\u0026ndash;4278). Written informed consent was obtained from all participants.\u003c/p\u003e \u003cp\u003e2.2 Treatment procedure\u003c/p\u003e \u003cp\u003eThe treatment plan used ICI (manufacturer unlimited; dosage according to the opinion of the attending physician) in combination with other treatments, including chemotherapy, radiotherapy, and targeted therapy. Following the completion of neoadjuvant combination immunotherapy, patients were restaged using chest, abdominal, and pelvic CT scans. Restaging with MRI, flexible endoscopy, and/or EUS was used to evaluate lesion regression. All the patients underwent laparoscopic or open surgery. For patients with distant metastases before treatment, if residual metastases were considered after treatment, a multidisciplinary consultation was conducted to determine the need for combined metastatic resection.\u003c/p\u003e \u003cp\u003e2.3 Data collection\u003c/p\u003e \u003cp\u003eThe data included basic patient information, such as sex, age, body mass index (BMI), family history, tumor location, preoperative imaging data, colonoscopy pathology data, carcinoembryonic antigen (CEA) level, hemoglobin (Hb) level, and neutrophil-to-lymphocyte ratio (NLR). Additionally, genetic testing of tumor tissues or blood samples, including MMR status, MSI status, and mutations in the KRAS, NRAS, BRAF, tp53, pole, and PIK3CA genes, was performed before treatment, if possible. Finally, the time intervals between the different treatment stages and postoperative pathological results, such as pathological tumor-node-metastasis (pTNM) staging and tumor regression grade (TRG), were analyzed.\u003c/p\u003e \u003cp\u003e2.4 Efficacy and safety evaluation\u003c/p\u003e \u003cp\u003eThe Dowrak/R\u0026ouml;del TRG system [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e] has four levels: (1) TRG-0 is no response; (2) TRG-1 is less than 25% fibrosis in the tumor; (3) TRG2 is 25%-50% fibrosis in the tumor; (3) TRG-3 is more than 50% fibrosis in the tumor; and (3) TRG-4 is complete remission. Consequently, pCR was defined as tumor regression induced by neoadjuvant combination immunotherapy without residual cancer or positive lymph nodes (pCR\u0026thinsp;=\u0026thinsp;TRG-4). AEs were assessed using the Common Adverse Event Evaluation Criteria (CTCAE) version 5.0, published by the US Department of Health and Human Services [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Immunity-related adverse events (irAEs) were evaluated according to literature standards [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e \u003cp\u003e2.5 Statistical analysis\u003c/p\u003e \u003cp\u003eStatistical analyses were performed using the IBM SPSS Statistics version 26 (IBM, Armonk, NY, USA). Categorical variables were compared using Pearson\u0026rsquo;s chi-square and Fisher\u0026rsquo;s exact tests, whereas continuous variables were analyzed using the Kruskal\u0026ndash;Wallis H-test. Statistical significance was set at p\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/p\u003e"},{"header":"3 Results","content":"\u003ch2\u003e3.1\u0026nbsp; \u0026nbsp; \u0026nbsp;Patient characteristics\u003c/h2\u003e\n\u003cp\u003eThis study included 81 patients with CRC who met the inclusion criteria between February 2015 and September 2023. A total of 33 patients (40.7%) achieved pCR, whereas 48 (59.3%) did not. A flowchart of the study is shown in \u003cstrong\u003eFigure 1\u003c/strong\u003e. The average age was 54.6\u0026plusmn;12.3 years, with a median BMI of 23.8 kg/m\u003csup\u003e2\u003c/sup\u003e (IQR 21.5-26.0), and a median CEA level of 4.0 ng/mL (IQR (1.8-17.2)) before treatment. Of the 81 patients, 44 were male (54.3%) and 37 were female (45.7%). Regarding the primary tumor site, 43 patients had rectal cancer (53.1%), 15 had sigmoid colon cancer (18.5%), and 23 had ascending colon cancer (28.4%). According to the clinical stage before treatment, 11 (13.6 %), 49 (60.5 %), and 21 (25.9 %) patients had stages II, III, and IV disease, respectively. According to MMR status, there were 24 cases of dMMR (29.6%) and 57 cases of pMMR (70.4%).\u003c/p\u003e\n\u003ch2\u003e3.2\u0026nbsp; \u0026nbsp; \u0026nbsp;Clinical and molecular predictors of pCR\u003c/h2\u003e\n\u003cp\u003ePatients with younger age (50 vs. 58 years; p = 0.003), low CEA level (2.1 vs 8.6; p \u0026lt; 0.001), high tumor mutational burden (TMB) level (68 vs. 5; p \u0026lt; 0.001) before treatment, clinical stage III (69.7% vs. 54.2%; p \u0026lt; 0.001), and no lymph node metastasis before treatment (24.2% vs. 6.3%; p = 0.049) were more likely to achieve pCR after receiving neoadjuvant combination immunotherapy. There were no significant differences in sex, BMI, family history, primary tumor site, NLR, Hb level, lesion length, or T stage before treatment between the pCR and non-pCR groups (p \u0026gt; 0.05) (\u003cstrong\u003eTable 1\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003eCombining the pathological, IHC, and genetic testing results of some patients before treatment, we found that patients with MSI-H (42.4% vs. 12.5%, p = 0.003), dMMR (48.5% vs. 18.7%, p = 0.002), and combined pole gene mutations (21.2% vs. 2.1%, p = 0.008) were more likely to achieve a pCR (p \u0026lt; 0.05). However, we did not find any statistically significant differences in tumor differentiation, Lynch syndrome, KRAS, NRAS, BRAF, TP53, or PIK3CA mutations between the pCR and non-pCR groups (\u003cstrong\u003eTable 2\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003eAmong 81 patients, the median time from diagnosis to the start of their first treatment was 28 days (IQR: 14-45.5). From the start of neoadjuvant therapy to its completion, the median time was 100 days (IQR: 71.5-145.5). Following neoadjuvant therapy, the median interval was 46 days (IQR: 34.5-63) until surgery. Notably, there were no significant differences in the time intervals between the pCR and non-pCR groups (\u003cstrong\u003eTable 3\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003eAmong these cases, 62 used PD-1 inhibitors, nine used PD-L1 inhibitors, and 10 used a combination of PD-1 and CTLA-4 inhibitors. Primary preoperative chemotherapy regimens included CAPOX (n = 71) and FOLFOX (n = 4). Additionally, 22 patients with rectal cancer underwent synchronous preoperative radiotherapy and chemotherapy. The chemotherapy regimen was primarily capecitabine, with 13 patients undergoing short-course radiotherapy (SCRT) and nine receiving long-course radiotherapy (LCRT). Furthermore, preoperative combination chemotherapy (p = 0.021) and targeted therapy (p = 0.01) affected postoperative pCR rates (\u003cstrong\u003eTable 3\u003c/strong\u003e).\u003c/p\u003e\n\u003ch2\u003e3.3\u0026nbsp; \u0026nbsp; \u0026nbsp;Postoperative pathological outcomes\u003c/h2\u003e\n\u003cp\u003eBased on MMR status, the 81 patients were categorized into two groups: dMMR (n = 24) and pMMR (n = 57). Remarkably, all patients achieved an objective response rate (ORR). In the dMMR group, a significantly higher proportion of patients achieved pCR than in the pMMR group (66.7% vs. 29.8%, p \u0026lt; 0.05). Additionally, the dMMR group exhibited a higher rate of postoperative N0 status than the pMMR group (83.3% vs. 61.4%, p = 0.20). Furthermore, the dMMR group had a lower incidence of vascular (12.5% vs. 22.8%, p = 0.43) and perineural invasion (12.5% vs. 29.8%, p = 0.099) than the pMMR group (\u003cstrong\u003eTable 4\u003c/strong\u003e).\u003c/p\u003e\n\u003ch2\u003e3.4\u0026nbsp; \u0026nbsp; \u0026nbsp;Neoadjuvant therapy- and surgical-related AEs\u003c/h2\u003e\n\u003cp\u003eThe overall AE rate associated with neoadjuvant chemoradiotherapy (nCRT) and neoadjuvant chemotherapy (NAC) was 70.3%. Among these reactions, 3-4 grade events account for 16.0%. In contrast, the total AE rate of neoadjuvant ICIs was 29.6%, with no observed 3-4 grade adverse reactions observed. The main irAEs were fever (4.9%), fatigue (4.9%), rash or pruritus (7.4%), and diarrhea (8.6%). In contrast, the AEs associated with nCRT/NAC predominantly included hand-and-foot syndrome (19.8%), nausea (17.3%), and vomiting (12.3%). Remarkably, after neoadjuvant combination immunotherapy and surgery, no 3-4 grade srAEs were observed. Instead, 1-2 grade AEs included blood loss \u0026gt;100 mL in seven cases, anastomotic leakage in two cases, ileus in one case, chylous fistula in one case, incisional hernia in one case, a perineal incision in three cases, and stoma infection in one case (\u003cstrong\u003eTable 5\u003c/strong\u003e).\u003c/p\u003e"},{"header":"4 Discussion","content":"\u003cp\u003eIn this single-center retrospective study, all patients received immunotherapy before surgery. After surgery, more than 40% of patients achieved pCR, with 66.7% and 29.8% of patients with dMMR and pMMR colorectal cancer achieving pCR, respectively. Additionally, this study suggests that the factors predicting pCR include younger age, lower CEA levels before treatment, clinical stage III, negative clinical lymph nodes, and molecular pathology including MSI-H, dMMR, pole gene mutations, and higher TMB levels.\u003c/p\u003e \u003cp\u003eThe traditional neoadjuvant treatment methods for colon cancer include chemotherapy, radiotherapy, targeted therapy, and combination therapy. Currently, neoadjuvant treatment for rectal cancer is based on a combination of radiotherapy and chemotherapy [\u003cspan additionalcitationids=\"CR13\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. The ORR of colorectal cancer with monotherapy is 40%, and the pCR rate is 5% [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. The pCR rate of combined radiotherapy and chemotherapy is 10\u0026ndash;15% [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Garcia-Aguilar et al. found that TNT therapy achieved pCR in 38% of rectal cancer patients [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Our research found that compared to traditional treatment methods, neoadjuvant combination immunotherapy can increase the rate of complete pathological remission after surgery, with more than 40% of patients achieving pCR, including 39.4 (13/43) of patients with rectal cancer who achieved pCR. This shows that neoadjuvant combination immunotherapy can improve the rate of pCR compared with traditional treatment methods. In addition, a Voltage study [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e] explored a new neoadjuvant immunotherapy with nivolumab after long-distance synchronous radiotherapy and chemotherapy for locally advanced rectal cancer. The pCR rate in the dMMR group was 60%, which is consistent with our results. Among 24 patients with dMMR, 16 (66.7%) achieved pCR. Lin et al. [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e] reported that the pCR rate in 26 patients with pMMR rectal cancer receiving short-term radiotherapy combined with camrelizumab and CapeOx was 46.2%. In our study, 29.8% (17/57) of patients achieved complete pathological remission. Because our study included both colon and rectal cancer cases and there were mixed factors, such as treatment plan, treatment cycle, small data volume, and tumor staging, the optimal treatment plan for combination therapy cannot be determined at present.\u003c/p\u003e \u003cp\u003eIn patients with pMMR or MSS CRC, the optimization of new neoadjuvant immunotherapy regimens and the identification of effective biomarkers to predict therapeutic efficacy are important research topics. Currently, a few potential markers such as POLE or POLD1 gene mutations, TMB, immune score, PD-L1 expression, CD8\u003csup\u003e+\u003c/sup\u003e/Treg ratio, and intestinal flora [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. In a study of patients with MSI-H mCRC receiving PD-1 and PD-L1 treatment, all 13 patients with high TMB achieved objective remission, whereas six of nine patients with low TMB experienced tumor progression [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Therefore, TMB is an effective biomarker; however, there is controversy over its optimal cutoff value when applied as a marker for predicting the efficacy of immunotherapy. Because different studies are based on different detection platforms and panels, they have different cutoff values. Determining the optimal cutoff value for TMB is another direction that should be explored in future studies. Colorectal tumors with POLE or POLD1 gene mutations are of the MSS type and can benefit from PD-1 monoclonal antibody treatment; however, this type of mutation accounts for only 1% of colorectal cancer cases [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. In a retrospective study using CEA levels to predict pCR, lower CEA levels were associated with pCR. Additionally, CEA levels before and after neoadjuvant therapy can be used to predict pCR [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Clinical staging is related to patient risk stratification, which distinguishes patient risk by analyzing patient images and pathological results combined with the T stage, N stage, and other factors. However, the specific application of these indicators to predict the efficacy of neoadjuvant therapy and to define the weight of each indicator requires further exploration.\u003c/p\u003e \u003cp\u003eAmong the 81 patients included in the study, AEs such as fever (4.9%), fatigue (4.9%), rash or pruritus (7.4%), and diarrhea (8.6%) were observed; however, there were no treatment-related deaths or severe adverse reactions. In the KEYNOTE-177 study [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e], the pembrolizumab group had a 31% incidence of immune- and infusion-related adverse reactions, of which 9% were grade 3 or 4, with colonic inflammation and hepatitis being the most common. The adverse reaction outcomes of this study were similar to those of the KEYNOTE-177 study; however, no grade 3\u0026ndash;4 AEs were observed, indicating that neoadjuvant immunotherapy for colorectal cancer is safe. Grade 1\u0026ndash;2 AEs caused by neoCRT/NAC included hand-and-foot syndrome (19.8%), nausea (17.3%), and vomiting (12.3%). In the NICHE study (2), 20% of the 40 patients who underwent colon resection surgery had grade III surgical complications, and the incidence of anastomotic leakage was as high as 10%, including five cases of abdominal (or incision) infection, one case of intestinal obstruction, one case of pneumonia, and one case of small intestinal injury; the high incidence of anastomotic leakage may be related to the combined use of PD-1 and CTLA-4. In this study, there were only two cases of anastomotic leakage after CRC surgery, both of which improved with conservative treatment. Seven patients had intraoperative bleeding of \u0026gt;\u0026thinsp;100 mL, one had ileus, one had a chylous fistula, one had an incisional hernia, three had a perineal incision, and one had a stoma infection; however, there were no perioperative deaths.\u003c/p\u003e \u003cp\u003eThis single-center, retrospective study has several limitations. First, the study only included patients with CRC who underwent surgical treatment and excluded patients who achieved complete clinical remission after neoadjuvant therapy, those whose disease progressed, and those who could not undergo surgery, which may have caused a selection bias. Second, the study included patients with colon and rectal cancers, including those with advanced CRC, and there were differences in the preoperative medication plans and cycles, which may have affected the statistical results. Finally, the sample size was relatively small. Further multicenter prospective studies with larger sample sizes are warranted.\u003c/p\u003e"},{"header":"5 Conclusion","content":"\u003cp\u003eNeoadjuvant combination immunotherapy has a favorable pCR rate in patients with CRC. Young age, pretreatment CEA level, TMB level, clinical stage, lymph node metastasis, MSI, MMR, and pole status can be used as indicators of the efficacy of neoadjuvant combination immunotherapy. No severe AEs were observed in the patients in this group, indicating that neoadjuvant combination immunotherapy is safe and reliable.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003ch2\u003eConflict of Interest\u003c/h2\u003e \u003cp\u003eWe declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eFunding\u003c/h2\u003e \u003cp\u003eThis study was supported by grants from the National Natural Science Foundation of China (no. 82072732) and the Beijing Natural Science Foundation (L222054, 4232058).\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eAll authors contributed to the study conception and design. Drafting the work and/or revising it critically: Yuegang Li, Meng Zhuang, Shiwen Mei, Wei Zhao and Wenlong Qiu. Final approval of the version to be published: Xishan Wang, and Jianqiang Tang. All authors contributed to the article and approved the submitted version.\u003c/p\u003e\u003ch2\u003eData Availability Statement\u003c/h2\u003e \u003cp\u003eThe raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eLenz HJ, Van Cutsem E, Luisa Limon M (2022) First-line nivolumab plus low-dose ipilimumab for microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer: The Phase II CheckMate 142 study. 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Ann Surg. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1097/SLA.0b013e3181b91e63\u003c/span\u003e\u003cspan address=\"10.1097/SLA.0b013e3181b91e63\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. .250:582\u0026thinsp;\u0026ndash;\u0026thinsp;89\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAndr\u0026eacute; T, Shiu KK, Kim TW (2020) Pembrolizumab in microsatellite-instability-high advanced colorectal cancer. N Engl J Med 383:2207\u0026ndash;2218. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1056/NEJMoa2017699\u003c/span\u003e\u003cspan address=\"10.1056/NEJMoa2017699\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1. Patient demographics and tumor characteristics before treatment.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"576\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.622540250447226%\" valign=\"top\"\u003e\n \u003cp\u003eCharacteristics\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.214669051878353%\" valign=\"top\"\u003e\n \u003cp\u003eTotal (n=81)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.214669051878353%\" valign=\"top\"\u003e\n \u003cp\u003epCR (n=33)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.214669051878353%\" valign=\"top\"\u003e\n \u003cp\u003eNon-pCR (n=48)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.73345259391771%\" valign=\"top\"\u003e\n \u003cp\u003eP value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.268551236749115%\" valign=\"top\"\u003e\n \u003cp\u003eAge, years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.964664310954063%\" valign=\"top\"\u003e\n \u003cp\u003e54.6\u0026plusmn;12.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.964664310954063%\" valign=\"top\"\u003e\n \u003cp\u003e49.5\u0026plusmn;13.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.731448763250885%\" valign=\"top\"\u003e\n \u003cp\u003e58.2\u0026plusmn;19.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.070671378091873%\" valign=\"top\"\u003e\n \u003cp\u003e0.003\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.268551236749115%\" valign=\"top\"\u003e\n \u003cp\u003eSex, male\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.964664310954063%\" valign=\"top\"\u003e\n \u003cp\u003e44(54.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.964664310954063%\" valign=\"top\"\u003e\n \u003cp\u003e19(57.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.731448763250885%\" valign=\"top\"\u003e\n \u003cp\u003e25(52,1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.070671378091873%\" valign=\"top\"\u003e\n \u003cp\u003e0.63\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.268551236749115%\" valign=\"top\"\u003e\n \u003cp\u003eBMI, kg/m\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.964664310954063%\" valign=\"top\"\u003e\n \u003cp\u003e23.8(21.5-26.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.964664310954063%\" valign=\"top\"\u003e\n \u003cp\u003e23.6(21.5-26.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.731448763250885%\" valign=\"top\"\u003e\n \u003cp\u003e24.1(21.1-26.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.070671378091873%\" valign=\"top\"\u003e\n \u003cp\u003e1.00\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.268551236749115%\" valign=\"top\"\u003e\n \u003cp\u003eFamily history of cancer\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;Yes\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;No\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.964664310954063%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e21(25.9)\u003c/p\u003e\n \u003cp\u003e60(74.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.964664310954063%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e7(21.2)\u003c/p\u003e\n \u003cp\u003e26(78.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.731448763250885%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e14(29.2)\u003c/p\u003e\n \u003cp\u003e34(70.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.070671378091873%\" valign=\"top\"\u003e\n \u003cp\u003e0.42\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.268551236749115%\" valign=\"top\"\u003e\n \u003cp\u003ePrimary tumor location\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;Ascending colon\u003c/p\u003e\n \u003cp\u003eSigmoid colon\u003c/p\u003e\n \u003cp\u003eRectum\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.964664310954063%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e23(28.4)\u003c/p\u003e\n \u003cp\u003e15(18.5)\u003c/p\u003e\n \u003cp\u003e43(53.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.964664310954063%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e13(39.4)\u003c/p\u003e\n \u003cp\u003e7(21.2)\u003c/p\u003e\n \u003cp\u003e13(39.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.731448763250885%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e10(20.8)\u003c/p\u003e\n \u003cp\u003e8(16.7)\u003c/p\u003e\n \u003cp\u003e30(62.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.070671378091873%\" valign=\"top\"\u003e\n \u003cp\u003e0.10\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.268551236749115%\" valign=\"top\"\u003e\n \u003cp\u003eClinical TNM stage\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;II\u003c/p\u003e\n \u003cp\u003eIII\u003c/p\u003e\n \u003cp\u003eIV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.964664310954063%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e11(13.6)\u003c/p\u003e\n \u003cp\u003e49(60.5)\u003c/p\u003e\n \u003cp\u003e21(25.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.964664310954063%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e8(24.2)\u003c/p\u003e\n \u003cp\u003e23(69.7)\u003c/p\u003e\n \u003cp\u003e2(6.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.731448763250885%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e3(6.2)\u003c/p\u003e\n \u003cp\u003e26(54.2)\u003c/p\u003e\n \u003cp\u003e19(39.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.070671378091873%\" valign=\"top\"\u003e\n \u003cp\u003e＜0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.268551236749115%\" valign=\"top\"\u003e\n \u003cp\u003eClinical T-stage\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;T3\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;T4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.964664310954063%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e36(44.4)\u003c/p\u003e\n \u003cp\u003e45(55.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.964664310954063%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e17(51.5)\u003c/p\u003e\n \u003cp\u003e16(48.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.731448763250885%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e19(39.6)\u003c/p\u003e\n \u003cp\u003e29(69.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.070671378091873%\" valign=\"top\"\u003e\n \u003cp\u003e0.29\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.268551236749115%\" valign=\"top\"\u003e\n \u003cp\u003eClinical N-stage\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;0\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;1\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.964664310954063%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e11(13.6)\u003c/p\u003e\n \u003cp\u003e49(60.5)\u003c/p\u003e\n \u003cp\u003e21(25.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.964664310954063%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e8(24.2)\u003c/p\u003e\n \u003cp\u003e19(57.6)\u003c/p\u003e\n \u003cp\u003e6(18.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.731448763250885%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e3(6.3)\u003c/p\u003e\n \u003cp\u003e30(62.5)\u003c/p\u003e\n \u003cp\u003e15(31.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.070671378091873%\" valign=\"top\"\u003e\n \u003cp\u003e0.049\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.268551236749115%\" valign=\"top\"\u003e\n \u003cp\u003eLength of lesion\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.964664310954063%\" valign=\"top\"\u003e\n \u003cp\u003e4.8(4.15-5.95)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.964664310954063%\" valign=\"top\"\u003e\n \u003cp\u003e4.6(3.8-5.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.731448763250885%\" valign=\"top\"\u003e\n \u003cp\u003e4.9(4.23-6.05)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.070671378091873%\" valign=\"top\"\u003e\n \u003cp\u003e0.395\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.268551236749115%\" valign=\"top\"\u003e\n \u003cp\u003eHb, g/L\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.964664310954063%\" valign=\"top\"\u003e\n \u003cp\u003e126.7\u0026plusmn;25.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.964664310954063%\" valign=\"top\"\u003e\n \u003cp\u003e127.2\u0026plusmn;27.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.731448763250885%\" valign=\"top\"\u003e\n \u003cp\u003e126.4\u0026plusmn;23.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.070671378091873%\" valign=\"top\"\u003e\n \u003cp\u003e0.89\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.268551236749115%\" valign=\"top\"\u003e\n \u003cp\u003eNLR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.964664310954063%\" valign=\"top\"\u003e\n \u003cp\u003e2.56(1.84-3.48)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.964664310954063%\" valign=\"top\"\u003e\n \u003cp\u003e2,73(2.15-3.64)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.731448763250885%\" valign=\"top\"\u003e\n \u003cp\u003e2.47(1.70-3.39)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.070671378091873%\" valign=\"top\"\u003e\n \u003cp\u003e0.19\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.268551236749115%\" valign=\"top\"\u003e\n \u003cp\u003eCEA, ug/L\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.964664310954063%\" valign=\"top\"\u003e\n \u003cp\u003e4.0(1.8-17.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.964664310954063%\" valign=\"top\"\u003e\n \u003cp\u003e2.1(1.4-14.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.731448763250885%\" valign=\"top\"\u003e\n \u003cp\u003e8.6(2.3-27.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.070671378091873%\" valign=\"top\"\u003e\n \u003cp\u003e＜0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.268551236749115%\" valign=\"top\"\u003e\n \u003cp\u003eTMB, mutation/Mb\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.964664310954063%\" valign=\"top\"\u003e\n \u003cp\u003e10.6(4.0-61.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.964664310954063%\" valign=\"top\"\u003e\n \u003cp\u003e68.0(25.0-188.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.731448763250885%\" valign=\"top\"\u003e\n \u003cp\u003e5.1(3.1-11.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.070671378091873%\" valign=\"top\"\u003e\n \u003cp\u003e＜0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAbbreviation: pCR,\u0026nbsp;pathological complete response; BMI, Body mass index; TNM, Tumor Node Metastasis; Hb, Hemoglobin; NLR, Neutrophil-lymphocyte ratio; CEA, Carcinoembryonic antigen; TMB, Tumor mutational burden\u003c/p\u003e\n\u003cp\u003e\u003csup\u003ea\u003c/sup\u003e44 cases with TMB values detected were included in the analysis.\u003c/p\u003e\n\u003cp\u003eTable 2. Pathologic Findings on pre-treatment biopsy\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"557\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"30.28673835125448%\" valign=\"top\"\u003e\n \u003cp\u003eCharacteristics\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.71326164874552%\" valign=\"top\"\u003e\n \u003cp\u003eTotal (n=81)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.71326164874552%\" valign=\"top\"\u003e\n \u003cp\u003epCR (n=33)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.25089605734767%\" valign=\"top\"\u003e\n \u003cp\u003eNon-pCR(n=48)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.03584229390681%\" valign=\"top\"\u003e\n \u003cp\u003eP value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"30.28673835125448%\" valign=\"top\"\u003e\n \u003cp\u003eHistological appearance\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;Well differentiated\u003c/p\u003e\n \u003cp\u003eModerately differentiated\u003c/p\u003e\n \u003cp\u003ePoorly differentiated\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.71326164874552%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e2(2.5)\u003c/p\u003e\n \u003cp\u003e14(17.3)\u003c/p\u003e\n \u003cp\u003e65(80.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.71326164874552%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e1(3.0)\u003c/p\u003e\n \u003cp\u003e5(15.2)\u003c/p\u003e\n \u003cp\u003e27(81.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.25089605734767%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e1(2.1)\u003c/p\u003e\n \u003cp\u003e9(18.7)\u003c/p\u003e\n \u003cp\u003e38(79.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.03584229390681%\" valign=\"top\"\u003e\n \u003cp\u003e0.89\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"30.28673835125448%\" valign=\"top\"\u003e\n \u003cp\u003eLynch syndrome\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;No\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;Unknown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.71326164874552%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e5(6.2)\u003c/p\u003e\n \u003cp\u003e31(38.3)\u003c/p\u003e\n \u003cp\u003e45(55.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.71326164874552%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e3(9.1)\u003c/p\u003e\n \u003cp\u003e13(39.4)\u003c/p\u003e\n \u003cp\u003e17(51.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.25089605734767%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e2(4.2)\u003c/p\u003e\n \u003cp\u003e18(37.5)\u003c/p\u003e\n \u003cp\u003e28(58.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.03584229390681%\" valign=\"top\"\u003e\n \u003cp\u003e0.62\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"30.28673835125448%\" valign=\"top\"\u003e\n \u003cp\u003eMSI status\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;MSS\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;MSI-High\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;Not tested\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.71326164874552%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e38(46.9)\u003c/p\u003e\n \u003cp\u003e20(24.7)\u003c/p\u003e\n \u003cp\u003e23(28.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.71326164874552%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e9(27.3)\u003c/p\u003e\n \u003cp\u003e14(42.4)\u003c/p\u003e\n \u003cp\u003e10(30.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.25089605734767%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e29(60.4)\u003c/p\u003e\n \u003cp\u003e6(12.5)\u003c/p\u003e\n \u003cp\u003e13(27.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.03584229390681%\" valign=\"top\"\u003e\n \u003cp\u003e0.003\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"30.28673835125448%\" valign=\"top\"\u003e\n \u003cp\u003eMMR status\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;dMMR\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;pMMR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.71326164874552%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e24(29.6)\u003c/p\u003e\n \u003cp\u003e57(70.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.71326164874552%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e16(48.5)\u003c/p\u003e\n \u003cp\u003e17(51.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.25089605734767%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e8(16.7)\u003c/p\u003e\n \u003cp\u003e40(83.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.03584229390681%\" valign=\"top\"\u003e\n \u003cp\u003e0.002\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"30.28673835125448%\" valign=\"top\"\u003e\n \u003cp\u003eAny mutation\u003c/p\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;No\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;Unknown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.71326164874552%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e48(59.3)\u003c/p\u003e\n \u003cp\u003e11(13.6)\u003c/p\u003e\n \u003cp\u003e22(27.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.71326164874552%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e17(51.5)\u003c/p\u003e\n \u003cp\u003e5(15.2)\u003c/p\u003e\n \u003cp\u003e11(33.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.25089605734767%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e31(64.6)\u003c/p\u003e\n \u003cp\u003e6(12.5)\u003c/p\u003e\n \u003cp\u003e11(22.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.03584229390681%\" valign=\"top\"\u003e\n \u003cp\u003e0.49\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"30.28673835125448%\" valign=\"top\"\u003e\n \u003cp\u003eKRAS status\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;Yes\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;No\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;Unknown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.71326164874552%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e30(37.0)\u003c/p\u003e\n \u003cp\u003e29(35.8)\u003c/p\u003e\n \u003cp\u003e22(27.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.71326164874552%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e10(30.3)\u003c/p\u003e\n \u003cp\u003e12(36.4)\u003c/p\u003e\n \u003cp\u003e11(33.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.25089605734767%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e20(41.7)\u003c/p\u003e\n \u003cp\u003e17(35.4)\u003c/p\u003e\n \u003cp\u003e11(22.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.03584229390681%\" valign=\"top\"\u003e\n \u003cp\u003e0.48\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"30.28673835125448%\" valign=\"top\"\u003e\n \u003cp\u003eNRAS status\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;Yes\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;No\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;Unknown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.71326164874552%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e5(6.2)\u003c/p\u003e\n \u003cp\u003e54(66.7)\u003c/p\u003e\n \u003cp\u003e22(27.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.71326164874552%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e2(6.1)\u003c/p\u003e\n \u003cp\u003e20(60.6)\u003c/p\u003e\n \u003cp\u003e11(33.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.25089605734767%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e3(6.3)\u003c/p\u003e\n \u003cp\u003e34(70.8)\u003c/p\u003e\n \u003cp\u003e11(22.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.03584229390681%\" valign=\"top\"\u003e\n \u003cp\u003e0.58\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"30.28673835125448%\" valign=\"top\"\u003e\n \u003cp\u003eBRAF status\u003c/p\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;No\u003c/p\u003e\n \u003cp\u003eUnknown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.71326164874552%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e9(11.1)\u003c/p\u003e\n \u003cp\u003e50(61.7)\u003c/p\u003e\n \u003cp\u003e22(27.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.71326164874552%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e2(6.1)\u003c/p\u003e\n \u003cp\u003e20(60.6)\u003c/p\u003e\n \u003cp\u003e11(33.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.25089605734767%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e7(14.6)\u003c/p\u003e\n \u003cp\u003e30(62.5)\u003c/p\u003e\n \u003cp\u003e11(22.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.03584229390681%\" valign=\"top\"\u003e\n \u003cp\u003e0.36\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"30.28673835125448%\" valign=\"top\"\u003e\n \u003cp\u003eTP53 mutation\u003c/p\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;No\u003c/p\u003e\n \u003cp\u003eUnknown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.71326164874552%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e23(28.4)\u003c/p\u003e\n \u003cp\u003e35(43.2)\u003c/p\u003e\n \u003cp\u003e23(28.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.71326164874552%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e8(24.2)\u003c/p\u003e\n \u003cp\u003e14(42.4)\u003c/p\u003e\n \u003cp\u003e11(33.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.25089605734767%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e15(31.2)\u003c/p\u003e\n \u003cp\u003e21(43.8)\u003c/p\u003e\n \u003cp\u003e12(25.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.03584229390681%\" valign=\"top\"\u003e\n \u003cp\u003e0.66\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"30.28673835125448%\" valign=\"top\"\u003e\n \u003cp\u003ePole status\u003c/p\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;No\u003c/p\u003e\n \u003cp\u003eUnknown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.71326164874552%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e8(9.9)\u003c/p\u003e\n \u003cp\u003e49(60.5)\u003c/p\u003e\n \u003cp\u003e24(29.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.71326164874552%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e7(21.2)\u003c/p\u003e\n \u003cp\u003e15(45.5)\u003c/p\u003e\n \u003cp\u003e11(33.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.25089605734767%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e1(2.1)\u003c/p\u003e\n \u003cp\u003e34(70.8)\u003c/p\u003e\n \u003cp\u003e13(27.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.03584229390681%\" valign=\"top\"\u003e\n \u003cp\u003e0.008\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"30.28673835125448%\" valign=\"top\"\u003e\n \u003cp\u003ePIK3CA status\u003c/p\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;No\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;Unknown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.71326164874552%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e12(14.8)\u003c/p\u003e\n \u003cp\u003e47(58.0)\u003c/p\u003e\n \u003cp\u003e22(27.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.71326164874552%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e5(15.2)\u003c/p\u003e\n \u003cp\u003e17(51.5)\u003c/p\u003e\n \u003cp\u003e11(33.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.25089605734767%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e7(14.6)\u003c/p\u003e\n \u003cp\u003e30(62.5)\u003c/p\u003e\n \u003cp\u003e11(22.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.03584229390681%\" valign=\"top\"\u003e\n \u003cp\u003e0.55\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAbbreviation: pCR,\u0026nbsp;pathological complete response; MSI, microsatellite instability; MSS, microsatellite stable; MMR, mismatch repair; dMMR, Mismatch repair deficient; pMMR, Mismatch repair proficient\u003c/p\u003e\n\u003cp\u003eTable 3. Neoadjuvant treatment characteristics\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"652\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.25192012288787%\" valign=\"top\"\u003e\n \u003cp\u003eVariable\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.357910906298002%\" valign=\"top\"\u003e\n \u003cp\u003eTotal (n=81)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.357910906298002%\" valign=\"top\"\u003e\n \u003cp\u003epCR (n=33)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.89400921658986%\" valign=\"top\"\u003e\n \u003cp\u003eNon-pCR(n=48)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.138248847926267%\" valign=\"top\"\u003e\n \u003cp\u003eP value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.25192012288787%\" valign=\"top\"\u003e\n \u003cp\u003eDays from diagnosis to initiation of any therapy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.357910906298002%\" valign=\"top\"\u003e\n \u003cp\u003e28(14-45.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.357910906298002%\" valign=\"top\"\u003e\n \u003cp\u003e35(16-52.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.89400921658986%\" valign=\"top\"\u003e\n \u003cp\u003e22(14-40)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.138248847926267%\" valign=\"top\"\u003e\n \u003cp\u003e0.13\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.25192012288787%\" valign=\"top\"\u003e\n \u003cp\u003eDays from initiation of any therapy to completion of all therapy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.357910906298002%\" valign=\"top\"\u003e\n \u003cp\u003e100(71.5-145.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.357910906298002%\" valign=\"top\"\u003e\n \u003cp\u003e100(75.5-137.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.89400921658986%\" valign=\"top\"\u003e\n \u003cp\u003e100.5(69.25-153)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.138248847926267%\" valign=\"top\"\u003e\n \u003cp\u003e0.91\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.25192012288787%\" valign=\"top\"\u003e\n \u003cp\u003eDays from completion of all therapy to surgery\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.357910906298002%\" valign=\"top\"\u003e\n \u003cp\u003e46(34.5-63)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.357910906298002%\" valign=\"top\"\u003e\n \u003cp\u003e49(35-61.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.89400921658986%\" valign=\"top\"\u003e\n \u003cp\u003e44.5(33.25-63.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.138248847926267%\" valign=\"top\"\u003e\n \u003cp\u003e0.79\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.25192012288787%\" valign=\"top\"\u003e\n \u003cp\u003eNeoadjuvant immunotherapy\u003c/p\u003e\n \u003cp\u003ePD-1 inhibitor\u003c/p\u003e\n \u003cp\u003ePD-L1 inhibitor\u003c/p\u003e\n \u003cp\u003ePD-1/CTLA-4 inhibitors\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.357910906298002%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e62(76.5)\u003c/p\u003e\n \u003cp\u003e9(11.3)\u003c/p\u003e\n \u003cp\u003e10(12.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.357910906298002%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e26(78.8)\u003c/p\u003e\n \u003cp\u003e2(6.1)\u003c/p\u003e\n \u003cp\u003e5(15.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.89400921658986%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e36(75.0)\u003c/p\u003e\n \u003cp\u003e7(14.6)\u003c/p\u003e\n \u003cp\u003e5(10.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.138248847926267%\" valign=\"top\"\u003e\n \u003cp\u003e0.43\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.25192012288787%\" valign=\"top\"\u003e\n \u003cp\u003eNAC\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;Yes\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;No\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.357910906298002%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e76(93.8)\u003c/p\u003e\n \u003cp\u003e5(6.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.357910906298002%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e28(84.8)\u003c/p\u003e\n \u003cp\u003e5(15.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.89400921658986%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e48(100)\u003c/p\u003e\n \u003cp\u003e0(0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.138248847926267%\" valign=\"top\"\u003e\n \u003cp\u003e0.021\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.25192012288787%\" valign=\"top\"\u003e\n \u003cp\u003eInitial NAC reduction/stop\u003c/p\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.357910906298002%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e15(20.0)\u003c/p\u003e\n \u003cp\u003e60(80.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.357910906298002%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e7(25.9)\u003c/p\u003e\n \u003cp\u003e20(74.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.89400921658986%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e8(16.7)\u003c/p\u003e\n \u003cp\u003e40(83.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.138248847926267%\" valign=\"top\"\u003e\n \u003cp\u003e0.34\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.25192012288787%\" valign=\"top\"\u003e\n \u003cp\u003eTarget therapy before surgery\u003c/p\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.357910906298002%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e28(34.6)\u003c/p\u003e\n \u003cp\u003e53(65.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.357910906298002%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e6(18.2)\u003c/p\u003e\n \u003cp\u003e27(81.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.89400921658986%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e22(45.8)\u003c/p\u003e\n \u003cp\u003e26(54.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.138248847926267%\" valign=\"top\"\u003e\n \u003cp\u003e0.01\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.25192012288787%\" valign=\"top\"\u003e\n \u003cp\u003enCRT\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;No\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.357910906298002%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e22(27.2)\u003c/p\u003e\n \u003cp\u003e59(72.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.357910906298002%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e11(33.3)\u003c/p\u003e\n \u003cp\u003e22(66.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.89400921658986%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e11(22.9)\u003c/p\u003e\n \u003cp\u003e37(77.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.138248847926267%\" valign=\"top\"\u003e\n \u003cp\u003e0.30\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.25192012288787%\" valign=\"top\"\u003e\n \u003cp\u003eType of nCRT \u0026nbsp;\u003c/p\u003e\n \u003cp\u003eLCRT\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;SCRT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.357910906298002%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e9(40.9)\u003c/p\u003e\n \u003cp\u003e13(59.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.357910906298002%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e3(27.3)\u003c/p\u003e\n \u003cp\u003e8(72.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.89400921658986%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e6(54.5)\u003c/p\u003e\n \u003cp\u003e5(45.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.138248847926267%\" valign=\"top\"\u003e\n \u003cp\u003e0.19\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAbbreviation: pCR,\u0026nbsp;pathological complete response; NAC, Neoadjuvant\u0026nbsp;chemotherapy;\u0026nbsp;nCRT,\u0026nbsp;Neoadjuvant chemoradiotherapy; LCRT, Long-course chemoradiotherapy; SCRT, Short-course chemoradiotherapy\u003c/p\u003e\n\u003cp\u003eTable 4. Pathological outcomes of 81 patients after surgery\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.36889692585895%\" valign=\"top\"\u003e\n \u003cp\u003eCharacteristics\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.305605786618443%\" valign=\"top\"\u003e\n \u003cp\u003edMMR (N=24)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.678119349005424%\" valign=\"top\"\u003e\n \u003cp\u003epMMR (N=57)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.64737793851718%\" valign=\"top\"\u003e\n \u003cp\u003eP value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.36889692585895%\" valign=\"top\"\u003e\n \u003cp\u003eORR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.305605786618443%\" valign=\"top\"\u003e\n \u003cp\u003e24/24(100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.678119349005424%\" valign=\"top\"\u003e\n \u003cp\u003e57/57(100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.64737793851718%\" valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.36889692585895%\" valign=\"top\"\u003e\n \u003cp\u003ePathological response rate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.305605786618443%\" valign=\"top\"\u003e\n \u003cp\u003e24/24(100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.678119349005424%\" valign=\"top\"\u003e\n \u003cp\u003e57/57(100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.64737793851718%\" valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.36889692585895%\" valign=\"top\"\u003e\n \u003cp\u003epCR rate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.305605786618443%\" valign=\"top\"\u003e\n \u003cp\u003e16/24(66.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.678119349005424%\" valign=\"top\"\u003e\n \u003cp\u003e17/57(29.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.64737793851718%\" valign=\"top\"\u003e\n \u003cp\u003e0.002\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.36889692585895%\" valign=\"top\"\u003e\n \u003cp\u003eTRG\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;1\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;2\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;3\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.305605786618443%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e3/24 (12.5)\u003c/p\u003e\n \u003cp\u003e1/24 (4.2)\u003c/p\u003e\n \u003cp\u003e4/24 (16.7)\u003c/p\u003e\n \u003cp\u003e16/24(66.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.678119349005424%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e8/57(14.0)\u003c/p\u003e\n \u003cp\u003e23/57(40.4)\u003c/p\u003e\n \u003cp\u003e9/57(15.8)\u003c/p\u003e\n \u003cp\u003e17/57(29.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.64737793851718%\" valign=\"top\"\u003e\n \u003cp\u003e0.004\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.36889692585895%\" valign=\"top\"\u003e\n \u003cp\u003ePathological T stage\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;ypT0\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;ypT1\u003c/p\u003e\n \u003cp\u003eypT2\u003c/p\u003e\n \u003cp\u003eypT3\u003c/p\u003e\n \u003cp\u003eypT4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.305605786618443%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e15/24(62.5)\u003c/p\u003e\n \u003cp\u003e1/24(4,2)\u003c/p\u003e\n \u003cp\u003e2/24(8.3)\u003c/p\u003e\n \u003cp\u003e2/24(8.3)\u003c/p\u003e\n \u003cp\u003e4/24(16.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.678119349005424%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e17/57(29.8)\u003c/p\u003e\n \u003cp\u003e4/57(7.0)\u003c/p\u003e\n \u003cp\u003e8/57(14.0)\u003c/p\u003e\n \u003cp\u003e16/57(28.1)\u003c/p\u003e\n \u003cp\u003e12/57(21.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.64737793851718%\" valign=\"top\"\u003e\n \u003cp\u003e0.08\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.36889692585895%\" valign=\"top\"\u003e\n \u003cp\u003ePathological N stage\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;ypN0\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;ypN1\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;ypN2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.305605786618443%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e20/24(83.3)\u003c/p\u003e\n \u003cp\u003e2/24 (8.3)\u003c/p\u003e\n \u003cp\u003e2/24 (8.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.678119349005424%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e35/57(61.4)\u003c/p\u003e\n \u003cp\u003e13/57(22.8)\u003c/p\u003e\n \u003cp\u003e9/57(15.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.64737793851718%\" valign=\"top\"\u003e\n \u003cp\u003e0.20\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.36889692585895%\" valign=\"top\"\u003e\n \u003cp\u003ePathological TNM stage\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;0\u003c/p\u003e\n \u003cp\u003eI\u003c/p\u003e\n \u003cp\u003eII\u003c/p\u003e\n \u003cp\u003eIII\u003c/p\u003e\n \u003cp\u003eIV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.305605786618443%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e16/24(66.7)\u003c/p\u003e\n \u003cp\u003e2/24(8.3)\u003c/p\u003e\n \u003cp\u003e1/24(4.2)\u003c/p\u003e\n \u003cp\u003e2/24(8.3)\u003c/p\u003e\n \u003cp\u003e3/24(12.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.678119349005424%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e17/57(29.8)\u003c/p\u003e\n \u003cp\u003e9/57(15.8)\u003c/p\u003e\n \u003cp\u003e7/57(12.3)\u003c/p\u003e\n \u003cp\u003e13/57(22.8)\u003c/p\u003e\n \u003cp\u003e11/57(19.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.64737793851718%\" valign=\"top\"\u003e\n \u003cp\u003e0.04\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.36889692585895%\" valign=\"top\"\u003e\n \u003cp\u003eVascular invasion\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.305605786618443%\" valign=\"top\"\u003e\n \u003cp\u003e3(12,5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.678119349005424%\" valign=\"top\"\u003e\n \u003cp\u003e13(22.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.64737793851718%\" valign=\"top\"\u003e\n \u003cp\u003e0.43\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.36889692585895%\" valign=\"top\"\u003e\n \u003cp\u003ePerineural invasion\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.305605786618443%\" valign=\"top\"\u003e\n \u003cp\u003e3(12.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.678119349005424%\" valign=\"top\"\u003e\n \u003cp\u003e17(29.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.64737793851718%\" valign=\"top\"\u003e\n \u003cp\u003e0.099\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAbbreviation: ORR, Objective response rate; pCR, Pathological complete response; TRG, Tumor regression grade; TNM, Tumor Node Metastasis; dMMR, Mismatch repair deficient; pMMR, Mismatch repair proficient\u003c/p\u003e\n\u003cp\u003eTable 5. Neoadjuvant therapy-related and surgical-related adverse events\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003eAdverse Events\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003enCRT/NAC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eneoICIs\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003eGrade 1-2\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003eGrade 3-4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003eGrade 1-2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003eGrade 3-4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003eAny\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003e44(54.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003e13(16.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003e24(29.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003eFever\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003e4(4.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003eFatigue\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003e4(4.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003eRash or pruritus\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003e6(7.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003eHand and foot syndrome\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003e16(19.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003e1(1.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003eNausea\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003e14(17.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003e9(11.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003eVomit\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003e10(12.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003e2(2.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003eAbdominal pain\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003e3(3.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003e1(1.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003eDiarrhea\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003e1(1.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003e1(1.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003e7(8.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003eBowel obstruction\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003e2(2.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003eAnal pain\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003e4(4.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003eUrinary tract pain\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003e1(1.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003eHyperthyroidism\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003e2(2.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003eHypothyroidism\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003e1(1.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003eAminotransferase increased\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003e3(3.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003eMyelosuppression\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003e8(9.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003e3(3.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.273056057866185%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"66.72694394213381%\" colspan=\"4\" valign=\"top\"\u003e\n \u003cp\u003esrAEs\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eGrade1-2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eGrade 3-4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003eBlood loss\u0026gt;100ml\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e7(8.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003eAnastomotic leakage\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e2(2.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003eIleus\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e1(1.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003eChylous fistula\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e1(1.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003eIncisional hernia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e1(1.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003ePerineal incision\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e3(42.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003eStoma infection\u003csup\u003ec\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e1(26.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAbbreviation: NAC, Neoadjuvant\u0026nbsp;chemotherapy;\u0026nbsp;nCRT,\u0026nbsp;Neoadjuvant chemoradiotherapy; neoICIs, Neoadjuvant immune checkpoint inhibitions; srAEs, Surgical-related adverse events\u003c/p\u003e\n\u003cp\u003ea: 70 cases with anastomoses, b: 7 cases underwent Mile\u0026rsquo;s surgery, c: 38 cases with stoma\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"colorectal neoplasms, pathological complete response, neoadjuvant combination immunotherapy, surgery, safety","lastPublishedDoi":"10.21203/rs.3.rs-4001747/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4001747/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose\u003c/h2\u003e \u003cp\u003eTo identify the clinical and molecular factors that effectively predict pathological complete response (pCR) and assess the safety of patients receiving neoadjuvant combination immunotherapy.\u003c/p\u003e\u003ch2\u003eMaterials and Methods\u003c/h2\u003e \u003cp\u003eThis retrospective study evaluated 81 patients with colorectal cancer (CRC) at a Chinese tertiary center between 2015 and 2023. The cohort included 24 patients with deficient mismatch repair (dMMR) tumors and 57 patients with proficient mismatch repair (pMMR) tumors. Patients were treated with a neoadjuvant combination of immunotherapy and surgery.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eWe enrolled 81 patients who were divided into pCR (39.3%) and non-pCR (79.7%) groups. The factors significantly associated with a higher pCR rate after neoadjuvant combination immunotherapy were younger age, low carcinoembryonic antigen (CEA) level, high tumor mutational burden (TMB) level before treatment, clinical stage III, absence of lymph node metastasis before treatment, MSI-H level, dMMR, and pole status mutation. Preoperative combined chemotherapy and targeted therapy also influenced the pCR rate. Neoadjuvant combination immunotherapy showed an overall adverse event (AE) rate of 29.6%, with none of grades 3\u0026ndash;4. Surgery-related adverse reactions (srAEs) were also absent for grades 3\u0026ndash;4, and 14 of the 81 patients experienced grade 1\u0026ndash;2 AEs.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eNeoadjuvant combination immunotherapy resulted in a favorable pCR rate in patients with CRC. Young age, pretreatment CEA level, TMB level, clinical stage, lymph node metastasis, MSI, MMR, and pole status can be used as indicators of the efficacy of neoadjuvant combination immunotherapy. The incidence of AEs from neoadjuvant combination immunotherapy and surgery was low, indicating that this regimen is safe and feasible.\u003c/p\u003e","manuscriptTitle":"Neoadjuvant Combination Immunotherapy for Colorectal Cancer: Clinical and Molecular Predictors of Pathological Complete Response and Safety Assessment","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-03-07 18:25:08","doi":"10.21203/rs.3.rs-4001747/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"1845abc4-9973-400c-8c35-56e0866ff884","owner":[],"postedDate":"March 7th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-06-28T00:51:24+00:00","versionOfRecord":[],"versionCreatedAt":"2024-03-07 18:25:08","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4001747","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4001747","identity":"rs-4001747","version":["v1"]},"buildId":"_2-kVJe1T_tPrBINL-cwx","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}