Multicenter real-world study on safety and efficacy of neoadjuvant therapy in combination with immunotherapy for colorectal cancer / 中华胃肠外科杂志

Objective: To provide reference and evidence for clinical application of neoadjuvant immunotherapy in patients with colorectal cancer through multicenter large-scale analysis based on real-world data in China. Methods: This was a retrospective multicenter case series study. From January 2017 to October 2021, data of 94 patients with colorectal cancer who received neoadjuvant immunotherapy in Peking University Cancer Hospital (55 cases), Union Hospital of Tongji Medical College of Huazhong University of Science and Technology (19 cases), Sun Yat-sen University Cancer Center (13 cases) and Changhai Hospital of Navy Medical University (7 cases) were retrospectively collected, including 48 males and 46 females. The median age was 58 years. Eighty-one cases were rectal cancer and 13 cases were colon cancer (2 cases of double primary colon cancer). Twelve cases were TNM staging II and 82 cases were stage III. Forty-six cases were well differentiated, 37 cases were moderately differentiated and 11 cases were poorly differentiated. Twenty-six patients (27.7%) with mismatch repair defects (dMMR) and microsatellite instability (MSI-H) were treated with immunotherapy alone, mainly programmed cell death protein-1 (PD-1); sixty-eight cases (72.3%) with mismatch repair proficient (pMMR) and microsatellite stability (MSS) were treated with immune combined with neoadjuvant therapy, mainly CapeOx (capecitabine+oxaliplatin) combined with PD-1 antibody plus long- or short-course radiotherapy, or PD-1 antibody combined with cytotoxic T lymphocyte associated antigen 4 (CTLA-4) antibody. Analysis and evaluation of adverse events during neoadjuvant immunotherapy were performed according to the National Cancer Institute Common Toxicity Standard version 3.0; the surgical complications were evaluated according to the Clavien-Dindo grading standard; the efficacy evaluation of neoadjuvant immunotherapy included the following indicators: major pathological remission (MPR) was defined as tumor regression induced by neoadjuvant therapy in pathology residual tumor ≤10%; pathological complete response (pCR) was defined as tumor regression induced by neoadjuvant therapy without residual tumor in pathology; the tumor response rate was disease control rate (DCR), namely the proportion of complete response (CR), partial response (PR) and stable disease (SD) in the whole group; the objective response rate (ORR) was CR+PR. Results: The median cycle of neoadjuvant immunotherapy was 4 (1-10) in whole group, and the incidence of immune-related adverse reactions was 37.2% (35/94), including 35 cases (37.2%) of skin-related adverse reactions, 21 cases (22.3%) of thyroid dysfunction and 8 cases (8.5%) of immune enteritis, of which grade III or above accounted for 1.1%. The median interval between completion of neoadjuvant therapy and surgery was 30 (21-55) days. There were 81 cases of radical resection of rectal cancer, 11 cases of radical resection of colon cancer, and 2 cases of colon cancer combined with other organ resection. The primary tumor resection of all the patients reached R0. The incidence of surgical-related complications was 22.3% (21/94), mainly anastomotic leakage (4 cases), pelvic infection (4 cases), abdominal effusion (3 cases), anastomotic stenosis (3 cases ) and abdominal and pelvic hemorrhage (2 cases). Grade I-II complications developed in 13 cases (13.8%), grade III and above complications developed in 8 cases (8.5%), no grade IV or above complications were found. During a median follow-up of 32 (1-46 ) months, DCR was 98.9% (93/94), ORR was 88.3 % (83/94), pCR was 41.5% (39/94), MPR was 60.6% (57/94). The pCR rate of 26 patients with dMMR and MSI-H undergoing simple immunotherapy was 57.7% (15/26), and MPR rate was 65.4% (17/26). The pCR rate of 68 pMMR and MSS patients undergoing combined immunotherapy was 35.3%(24/68), and MPR rate was 58.8% (40/68). Conclusions: Neoadjuvant immunotherapy has favorable tumor control rate and pathological remission rate for patients with initial resectable colorectal cancer. The incidences of perioperative adverse reactions and surgical complications are acceptable.

Immunotherapy for microsatellite-instability-high advanced colorectal cancer / 中华胃肠外科杂志

Microsatellite instability-high (MSI-H) colorectal cancer accounts for approximately 10%-15% of all colorectal cancer patients, while in metastatic diseases the MSI-H population accounts for only 5% of patients. Previous studies have shown that early-stage MSI-H colorectal cancer patients have a good prognosis, but those with advanced disease have a poor prognosis and are not sensitive to chemotherapy. The advent of PD-1 antibodies has significantly improved the prognosis and changed treatment landscape in this population, not only achieving good outcomes in late-line therapy, but also significantly outperforming traditional chemotherapy combined with targeted therapy in first-line therapy. How to overcome primary and secondary drug resistance is a key issue in improving the outcome of MSI-H metastatic colorectal cancer, and commonly used approaches include changing chemotherapy regimens, combining with other immunotherapies, combining with anti-angiogenesis, and local treatments (surgery, radiotherapy, or interventional therapy). It is worth noting that immunotherapy has certain lifelong or even lethal toxicity, and the indications for neoadjuvant immunotherapy must be evaluated with caution. Neoadjuvant immunotherapy in MSI-H advantaged population can achieve high rates of pathological complete remission (pCR) and clinical complete remission (cCR). Therefore, for MSI-H patients with a strong intention to preserve anal sphincter and a strict evaluation of cCR after neoadjuvant immunotherapy, the Watch-and-Wait strategy offers an opportunity to preserve sphincter function and improve long-term survival quality in a subset of mid-to-low rectal cancers. Research on adjuvant immunotherapy in the field of colorectal cancer is also in full swing, and the results are worth waiting for.

CCR6 Is a Predicting Biomarker of Radiosensitivity and Potential Target of Radiosensitization in Rectal Cancer / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: This study aimed to explore the functions and mechanisms of C-C motif chemokine receptor 6 (CCR6), a gene associated with progression and metastasis of colorectal cancer (CRC), in radiosensitivity of rectal cancer (RC). MATERIALS AND METHODS: RNA sequencing and immunohistochemical analysis on CCR6 expression were performed in pretreatment tissues of RC patients exhibiting different therapeutic effects of radiotherapy. Colonogenic survival assay was conducted in different CRC cell lines to assess their radiosensitivity. And the impact of CCR6 expression on radiosensitivity was validated through RNA interference. The DNA damage repair (DDR) abilities of cell lines with different CCR6 expression were evaluated through immunofluorescence-based γH2AX quantification. RESULTS: The CCR6 mRNA level was higher in patients without pathologic complete remission (pCR) than in those with pCR (fold changed, 2.11; p=0.004). High-level expression of CCR6 protein was more common in the bad responders than in the good responders (76.3% vs. 37.5%, p < 0.001). The CRC cell lines with higher CCR6 expression (LoVo and sw480) appeared to be more radioresistant, compared with the sw620 cell line which had lower CCR6 expression. CCR6 knockdown made the LoVo cells more sensitive to ionizing radiation (sensitization enhancement ratio, 1.738; p < 0.001), and decreased their DDR efficiency. CONCLUSION: CCR6 might affect the RC radiosensitivity through DDR process. These findings supported CCR6 as a predicting biomarker of radiosensitivity and a potential target of radiosensitization for RC patients.

Surgery with versus without preoperative concurrent chemoradiotherapy for mid/low rectal cancer: an interim analysis of a prospective, randomized trial / 癌症

<p><b>INTRODUCTION</b>Multimodality therapy, including preoperative chemoradiotherapy (CRT) and total mesorectal excision (TME), has effectively reduced local recurrence rates of rectal cancer over the past decade. However, the benefits and risks of the addition of neoadjuvant CRT to surgery need to be evaluated. This study was to compare the efficacy of TME with versus without preoperative concurrent chemoradiotherapy (CCRT) involving XELOX regimen (oxaliplatin plus capecitabine) in Chinese patients with stages II and III mid/low rectal adenocarcinoma.</p><p><b>METHODS</b>We randomly assigned patients to the TME group (TME without preoperative CCRT) or CCRT + TME group (TME with preoperative CCRT). The primary endpoint was disease-free survival (DFS); the secondary endpoints were overall survival (OS), local and distant recurrence, tumor response to CRT, toxicity, sphincter preservation, and surgical complications. An interim analysis of the potential inferiority of DFS in the CCRT + TME group was planned when the first 180 patients had been followed up for at least 6 months.</p><p><b>RESULTS</b>A total of 94 patients in the TME group and 90 patients in the CCRT + TME group were able to be evaluated. The 3-year DFS and OS rates were 86.3 % and 91.5 % in the whole cohort, respectively. The 3-year DFS rates of the TME and CCRT + TME groups were 85.7% and 87.9 % (P = 0.766), respectively, and the 3-year OS rates were 90.7 % and 92.3 % (P = 0.855), respectively. The functional sphincter preservation rates of the TME and CCRT + TME groups were 71.3 % and 70.0 % (P = 0.849), respectively. In the TME group, 16 (17.0 %) patients were proven to have pTNM stage I disease after surgery. In the CCRT + TME group, 32 (35.6 %) patients achieved a pathologic complete response (pCR).</p><p><b>CONCLUSIONS</b>Preliminary results indicated no significant differences in the DFS, OS, or functional sphincter preservation rates between the TME and CCRT + TME groups. However, preoperative CCRT with XELOX yielded a high pCR rate. Newer techniques are needed to improve the staging accuracy, and further investigation is warranted.</p><p><b>CLINICAL TRIAL REGISTRATION NUMBER</b>Chi CTR-TRC-08000122.</p>

Expression of molecular markers detected by immunohistochemistry and risk of lymph node metastasis in stage T1 and T2 colorecrectal cancers / 中华肿瘤杂志

<p><b>OBJECTIVE</b>To study the molecular risk factors of lymph node metastasis in stage T1 and T2 colorectal cancers by tissue microarray and immunohistochemistry techniques.</p><p><b>METHODS</b>Two hundred and three patients with stage T1 and T2 colorectal carcinoma who underwent radical surgery from 1999 to 2010 in our department were included in this study. Their clinicopathological data were retrospectively analyzed. Expression of the following 14 molecular markers were selected and assayed by tissue microarray and immunohistochemistry: VEGFR-3, HER2, CD44v6, CXCR4, TIMP-1, EGFR, IGF-1R, IGF-2, IGFBP-1, ECAD, MMP-9, RKIP, CD133, MSI. Chi-squared test and logistic regression were used to evaluate the variables as potential risk factors for lymph node metastasis.</p><p><b>RESULTS</b>The positive expression rates of biomarkers were as following: VEGFR-3 (44.3%), EGFR (30.5%), HER-2 (28.1%), IGF-1R (63.5%), IGF-2 (44.8%), IGFBP-1 (70.9%), ECAD (45.8%), CD44v6 (51.2%), MMP-9 (44.3%), TIMP-1 (41.4%), RKIP (45.3%), CXCR4 (40.9%), and CD133 (49.8%). The positive rate of MSI expression was 22.2%. Both univariate and multivariate analyses showed that VEGFR-3, HER-2, and TIMP-1 were significant predictors of lymph node metastasis. Univariate analysis showed that CD44v6 and CXCR4 were significant significant predictors of lymph node metastasis.</p><p><b>CONCLUSIONS</b>VEGFR-3, HER2 and TIMP-1 are independent factors for lymph node metastasis in stage T1 and T2 colorectal cancers.</p>

Compliance and associated factors of postoperative chemotherapy for elderly patients with colorectal cancer / 中华胃肠外科杂志

<p><b>OBJECTIVE</b>To investigate the compliance and associated factors of postoperative chemotherapy for elderly patients with colorectal cancer.</p><p><b>METHODS</b>A total of 386 elderly patients (>70 years old) with stage II(-IIII( colorectal cancer underwent surgery between January 2000 and January 2010. The clinicopathological data were retrospectively reviewed. There were 226 patients received postoperative chemotherapy and 160(41.4%) refused. Logistic regression model was used to analyze factors associated with patients compliance to chemotherapy. Patients were followed up by phone call regarding the reason for refusal.</p><p><b>RESULTS</b>Multivariate analysis showed that gender, body mass index (BMI), body surface area (BSA), age, and complication were independent risk factors associated with chemotherapy compliance(All P<0.05). Follow-up phone questionnaire showed that 63.8%(51/80) of patients with stage II( cancer did not received chemotherapy because of the doctor's uncertainty of chemotherapy benefit. For stage III( patients, fear of chemotherapy (31.2%, 15/48), feeling uncomfortable (18.8%, 9/48), and financial issues(18.8%, 9/48) were the main factors. The desperate feeling was the predominant reason for stage IIII( patients(56.2%, 18/32).</p><p><b>CONCLUSIONS</b>Gender, BSA, age, and postoperative complication are the main factors associated with compliance to postoperative chemotherapy. Doctors' recommendation should be emphasized for stage II( patients. For stage III( patients, treatment recommendation should be enthusiastic.</p>

A multivariate analysis of prognostic determinants for stages II and III colorectal cancer in 141 patients / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Previous prognosis analyses of colorectal cancer (CRC) patients with stage II and III disease were done as separate categories. The purpose of this study was to analyze prognostic factors associated with survival in a group of patients who underwent radical resection of stages II and III CRC.</p><p><b>METHODS</b>A retrospective review was performed for 141 consecutive stages II and III patients who had undergone radical resection of colorectal adenocarcinoma between May 2003 and November 2003. Univariate and multivariate analyses were performed to assess the effect of record variables on disease free survival and overall survival.</p><p><b>RESULTS</b>The median follow-up time was 59 months, and the 3- and 5-year survival rates were 76% and 68%, respectively. Four factors were independently associated with a worse disease-free survival: diabetes (hazard ratio (HR) 2.338; 95% confidence interval (CI) 1.011 - 5.407), expression of cyclooxygenase-2 (Cox-2) (HR 0.335; 95%CI 0.126 - 0.888), expression of matrix metalloproteinases 2 (MMP-2) (HR 0.233; 95%CI 0.101 - 0.541), expression of vascular endothelial growth factor (VEGF) (HR 0.295; 95%CI 0.088 - 0.996). Four factors were independently associated with a worse overall survival: lymph nodes metastasis (HR 1.67; 95%CI 1.29 - 2.14), Cox-2 positive (HR 0.056; 95%CI 0.247 - 0.731), MMP-2 positive (HR 0.398; 95%CI 0.190 - 0.836), VEGF (HR 0.364; 95%CI 0.090 - 0.716).</p><p><b>CONCLUSIONS</b>Diabetes, expression of Cox-2, MMP-2 and VEGF were independently associated with a worse disease- free survival. Lymph nodes metastasis, expression of Cox-2, MMP-2 and high level of VEGF predicted a poor overall survival.</p>

Surgical treatment for 140 patients with gastric stromal tumors / 中华胃肠外科杂志

<p><b>OBJECTIVE</b>To analyze the outcome of the patients with gastric gastrointestinal stromal tumor(GIST) after surgical treatment and identify the associated risk factors.</p><p><b>METHODS</b>Clinical data and the tissue slices including immunohistochemistry staining of 140 patients with gastric GIST from January 1990 to December 2008 were retrospectively reviewed. SPSS 16.0 for Windows software package was used for statistical analysis.</p><p><b>RESULTS</b>The overall survival rates of 1-, 3-, 5-year were 96.8%, 86.7% and 79.3%, respectively. The survival rates of 1-, 3-, 5-year were 98.1%, 90.0% and 85.4% in patients who underwent complete tumor resection. But the survival rates of 1-, 3-, 5-year were 38.1%, 0 and 0 in patients with incomplete tumor resection. The differences were statistically significant (P<0.05). Gender, preoperative metastasis, tumor size,pathology type,karyokinesis, recurrence and metastasis were associated with survival rates in patients with complete tumor resection by univariate analysis. However, only tumor size, karyokinesis, recurrence and metastasis were associated with survival rates by Cox regression multivariable analysis(P<0.05).</p><p><b>CONCLUSION</b>Surgery remains the main treatment for gastric GIST. Local complete resection is the principal treatment.</p>

Surgical treatment for gastrointestinal stromal tumor / 中华外科杂志

<p><b>OBJECTIVE</b>To analyze the effects of surgical treatment for gastrointestinal stromal tumors (GISTs) and influential factors of survival.</p><p><b>METHODS</b>The clinical data and the tissue slices including immunohistochemical staining of 153 cases of GISTs from January 1990 to March 2006 were rechecked retrospectively. All patients were followed up carefully. More attention was paid to the surgical effects and the influential factors of survival.</p><p><b>RESULTS</b>The overall survival rates at 1-, 2-, 3-, 4- and 5-year were 94.9%, 83.3%, 73.3%, 70.5% and 64.3%, respectively. The median survival time for patients with tumor resected completely was 66.0 months, and the 2- and 5-year survival rate were 89.4% and 70.9% respectively. The median survival time was 23.8 months for the patients with tumor resected partly, and only two of these patients survived over 2 years. Gender, tumor sites, preoperative metastasis, tumor size, pathological type, karyokinesis and recurrence and metastasis were related with survival rates for the patients with tumor resected completely on univariate analysis, but tumor size, pathology type, recurrence and metastasis were related with survival rates on Cox regression multivariate analysis (P < 0.05).</p><p><b>CONCLUSIONS</b>Surgery should still be the main therapy for GISTs. Local complete resection is the principal treatment. The survival cannot be improved by extensive resection and lymph nodes clearance.</p>

Clinical features and treatment of 49 patients with anal canal adenocarcinoma / 中华胃肠外科杂志

<p><b>OBJECTIVE</b>To investigate the clinical features and treatment of anal canal adenocarcinoma.</p><p><b>METHODS</b>Clinical data of 49 patients with anal canal adenocarcinoma treated in our hospital from January 1965 to March 2002 were analyzed retrospectively.</p><p><b>RESULTS</b>The ratio of male to female was 1.3. The median age was 56 years old. Anal bleeding, tapering stool and anal lump were the most common symptoms. Chronic perianal diseases were complicated in 36.7% of the cases. The median follow-up was 66 months. Local recurrence and inguinal lymph node metastasis were found in 7 cases respectively, lung metastasis in 2, supraclavicular and mediastinal metastasis in 1 respectively. The 3-year survival rates in the patients with resection alone, radiochemotherapy alone, resection combined with radiochemotherapy, and without any treatment were 41.3%, 20.0%, 56.3% and 15.0%, respectively, and the 5-year survival rates were 34.4%, 0, 37.5%, 0, respectively.</p><p><b>CONCLUSIONS</b>Anal canal adenocarcinoma is a rare and fatal malignancy. Abdomino-perineal resection combined with postoperative radiochemotherapy is the principal treatment.</p>

Long- term results after radical resection in patients with rectal cancer / 中华胃肠外科杂志

<p><b>OBJECTIVE</b>To analyze the long- term results of radical resection for rectal cancer and the factors influencing the operative results.</p><p><b>METHODS</b>From January 1990 to December 1999, clinical data of 689 patients who underwent radical resection for rectal cancer were analyzed retrospectively.</p><p><b>RESULTS</b>The overall operative mortality was 0.7%, the follow- up rate was 96.7%, the median survival rate was 67.4 months. The 1-, 3-, 5- and 10-year survival rate after operation was 89.9%, 77.3%, 69.6% and 63.3% respectively. Univariate analysis showed that the survival rate was related with the first onset symptom, tumor location, infiltrated circumference of intestine, T staging, Dukes staging, histological type, extent of lymph node metastasis and operative approaches. Multivariate analysis showed that tumor location, histological type, invasive depth and Dukes staging were independent prognostic factors.</p><p><b>CONCLUSIONS</b>The long-term efficacy after radical resection for rectal cancer is correlated with tumor location, histological type, invasive depth and Dukes staging.</p>

Comparing the effect of adjuvant chemotherapy by portal vein infusion with intraluminal chemotherapy for colorectal cancer / 中华外科杂志

<p><b>OBJECTIVE</b>To compare the effect of 5-fluorouracil (5-FU) portal vein infusion (PVI) for 7 days after radical resection, with intraluminal chemotherapy during operation for eliminating liver metastasis and elevating long-term prognosis in colorectal cancer.</p><p><b>METHODS</b>162 colorectal cancer patients with radical resection were divided into portal vein chemotherapy group (group A, 82 cases) and intraluminal chemotherapy group (group B, 80 cases) randomly. In group A, 5-fluorouracil were infused with 1g per day constantly for 7 days after operation through portal vein catheters, which placed into greater omental vein and fixed on the abdominal wall. In group B, intraluminal chemotherapy was given and 5-fluorouracil 0.5 g was injected into the greater omental vein during operation.</p><p><b>RESULTS</b>The short-term complications and long-term effect in the two groups were compared by statistical software SPSS 8.0. Group A had more operative complications, and no statistical differences was found in hospital time and survival rate of the two groups. The 5-year survival rate is 76.7% (group A: 74.3%, group B: 79.2%), and the liver metastasis rate is 19.8%. There is no significant difference between the two group-survival curves. Multiple variable analysis suggested that Dukes' stage was the prognosis factor (P < 0.05).</p><p><b>CONCLUSIONS</b>The present study demonstrated that the two chemotherapy methods play an important role in preventing liver metastasis and improving the survival rate, and the intraluminal chemotherapy would be easier and simpler. The result should be further improved by using combined chemotherapy.</p>