Neoadjuvant Chemotherapy With Oxaliplatin and Fluoropyrimidine Versus Upfront Surgery for Locally Advanced Colon Cancer: The Randomized, Phase III OPTICAL Trial.

PURPOSE: The role of neoadjuvant chemotherapy (NAC) in colon cancer remains unclear. This trial investigated whether 3 months of modified infusional fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) or capecitabine and oxaliplatin (CAPOX) as NAC could improve outcomes in patients with locally advanced colon cancer versus upfront surgery. PATIENTS AND METHODS: OPTICAL was a randomized, phase III trial in patients with clinically staged locally advanced colon cancer (T3 with extramural spread into the mesocolic fat ≥5 mm or T4). Patients were randomly assigned 1:1 to receive six preoperative cycles of mFOLFOX6 or four cycles of CAPOX, followed by surgery and adjuvant chemotherapy (NAC group), or immediate surgery and the physician's choice of adjuvant chemotherapy (upfront surgery group). The primary end point was 3-year disease-free survival (DFS) assessed in the modified intention-to-treat (mITT) population. RESULTS: Between January 2016 and April 2021, of the 752 patients enrolled, 744 patients were included in the mITT analysis (371 in the NAC group; 373 in the upfront surgery group). At a median follow-up of 48.0 months (IQR, 46.0-50.1), 3-year DFS rates were 82.1% in the NAC group and 77.5% in the upfront surgery group (stratified hazard ratio [HR], 0.74 [95% CI, 0.54 to 1.03]). The R0 resection was achieved in 98% of patients who underwent surgery in both groups. Compared with upfront surgery, NAC resulted in a 7% pathologic complete response rate (pCR), significantly lower rates of advanced tumor staging (pT3-4: 77% v 94%), lymph node metastasis (pN1-2: 31% v 46%), and potentially improved overall survival (stratified HR, 0.44 [95% CI, 0.25 to 0.77]). CONCLUSION: NAC with mFOLFOX6 or CAPOX did not show a significant DFS benefit. However, this neoadjuvant approach was safe, resulted in substantial pathologic downstaging, and appears to be a viable therapeutic option for locally advanced colon cancer.

Tumor Deposits and Perineural Invasion had Comparable Impacts on the Survival of Patients With Non-metastatic Colorectal Adenocarcinoma: A Population-Based Propensity Score Matching and Competing Risk Analysis.

BACKGROUND: Both tumor deposits (TD) and perineural invasion (PNI) have been identified as risk factors for poor survival in patients with non-metastatic colorectal adenocarcinoma (CRC). However, the adverse impacts of TD and PNI on the survival of patients with non-metastatic CRC have not been compared. METHOD: Patients with non-metastatic CRC with known TD and PNI status were selected from the Surveillance, Epidemiology, and End Results (SEER) database. First, bivariate logistic regression analysis was utilized to identify the factors associated with TD and PNI status. Then, patients were divided into four groups, according to TD and PNI status. Propensity score matching (PSM) was performed to balance the baseline covariates. The impact of TD and PNI on survival was assessed by analyzing overall survival (OS) and cancer-specific mortality (CSM) rates. OS was calculated by the Kaplan-Meier method with log-rank analysis. CSM was estimated by competing risk analysis using the Fine and Gray model. RESULTS: A total of 70 689 patients with CRC met the inclusion and exclusion criteria. The positive rates of TD and PNI were 9.37% and 9.91%, respectively. For TD, the most important risk factor was N stage. With respect to PNI, the most significant factor was T stage. Tumor location, tumor size, differentiation grade, and serum CEA level were also correlated with TD and PNI status. After PSM, 1849 pairs were selected. Patients with TD+PNI+ status had the worst 5 year CSM and 5 year OS. In addition, the long-term survival outcomes of patients with TD+PNI- and TD-PNI+ status were comparable. CONCLUSION: The adverse impacts of TD and PNI on the survival of patients with non-metastatic CRC were comparable. CRC patients with both TD and PNI positive had the worst survival outcome.

Optimal examined lymph node count in node-negative colon cancer should be determined.

Background: We aimed to investigate the association between optimal examined lymph node (ELNs) and overall survival to determine the optimal cutoff point. Methods: Cox models and locally weighted scatterplot smoothing were used to fit hazard ratios and explore an optimal cutoff point based on the Chow test. Results: Overall survival increased significantly with the corresponding increase in the number of ELNs after adjusting for covariates. In Chow's test, the optimal cutoff point for node-negative colon cancer was 15, which was validated in both cohorts after controlling for confounders (Surveillance, Epidemiology, and End Results database: hazard ratio: 0.701, p < 0.001; single-center: HR: 0.563; p = 0.031). Conclusions: We conservatively suggest that the optimal number of ELNs for prognostic stratification is 15 in node-negative colon cancer.

Lay abstract Over the past 20 years, the number of examined lymph nodes (ELNs) has been an important indicator to accurately assess lymph node metastasis, and therefore, many studies have focused on exploring an optimal cutoff point to prevent missed detection of positive lymph nodes. However, in recent years, ELNs has been considered to play other key roles. In the current study, ELNs were deemed an important prognostic factor, and the minimum number of ELNs was recommended to be 15 in node-negative colon cancer via rigorous statistical methods and a large sample of data.

Neoadjuvant Modified FOLFOX6 With or Without Radiation Versus Fluorouracil Plus Radiation for Locally Advanced Rectal Cancer: Final Results of the Chinese FOWARC Trial.

PURPOSE: In the multicenter, open-label, phase III FOWARC trial, modified infusional fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) plus radiotherapy resulted in a higher pathologic complete response rate than fluorouracil plus radiotherapy in Chinese patients with locally advanced rectal cancer. Here, we report the final results. METHODS: Adults ages 18 to 75 years with stage II/III rectal cancer were randomly assigned (1:1:1) to five cycles of infusional fluorouracil (leucovorin 400 mg/m2, fluorouracil 400 mg/m2, and fluorouracil 2.4 g/m2 over 48 hours) plus radiotherapy (46.0 to 50.4 Gy delivered in 23 to 25 fractions during cycles 2 to 4) followed by surgery and seven cycles of infusional fluorouracil, the same treatment plus intravenous oxaliplatin 85 mg/m2 on day 1 of each cycle (mFOLFOX6), or four to six cycles of mFOLFOX6 followed by surgery and six to eight cycles of mFOLFOX6. The primary end point was 3-year disease-free survival (DFS). RESULTS: In total, 495 patients were randomly assigned to treatment. After a median follow-up of 45.2 months, DFS events were reported in 46, 39, and 46 patients in the fluorouracil plus radiotherapy, mFOLFOX6 plus radiotherapy, and mFOLFOX6 arms. In each arm, the probability of 3-year DFS was 72.9%, 77.2%, and 73.5% (P = .709 by the log-rank test), the 3-year probability of local recurrence after R0/1 resection was 8.0%, 7.0%, and 8.3% (P = .873 by the log-rank test), and the 3-year overall survival rate was 91.3%, 89.1%, and 90.7% (P = .971 by log-rank test), respectively. CONCLUSION: mFOLFOX6, with or without radiation, did not significantly improve 3-year DFS versus fluorouracil with radiation in patients with locally advanced rectal cancer. No significant difference in outcomes was found between mFOLFOX6 without radiotherapy and fluorouracil with radiotherapy, which requires additional investigation of the role of radiotherapy in these regimens.

[Use of C response protein in predicting postoperative anastomotic leakage in patients with rectal cancer].

OBJECTIVE: To investigate the value and feasibility of C reactive protein (CRP) in predicting postoperative anastomotic leakage in rectal cancer patients with enhanced recovery after surgery (ERAS) for safer implementation of this ERAS. METHODS: A cohort study on serum CRP of 455 rectal cancer patients undergoing laparoscopic radical resection according to the ERAS procedure at Gastrointestinal Unit of General Surgery Department, Guangdong General Hospital from August 2014 to June 2017 was retrospectively carried out. The serum CRP level was measured before operation and at postoperative days 1-7, and the serum CRP level of the groups with and without anastomotic leakage was compared to analyze its prediction for anastomotic leakage. Diagnostic standard of anastomotic leakage was based on the definition of postoperative anastomotic leakage in rectal cancer from International Study Group of Rectal Cancer (ISREC): (1) Postoperative localized or diffuse peritonitis occurred, or fecal liquid was found from the abdominal drainage tube; (2) When anastomotic leakage was uncertain, peritoneal or pelvic computed tomography scan should be used to confirm. RESULTS: All the 455 patients underwent surgery successfully, and 41 patients (9.0%) had anastomotic leakage postoperatively. Patients with anastomotic leakage were diagnosed (4.0±2.0) days postoperatively, of whom 8 cases (19.5%) were diagnosed more than 5 days postoperatively. Serum CRP levels in patients with anastomotic leakage continued to increase within 1-4 days postoperatively [(50.04±27.98) mg/L to (122.75±52.98) mg/L] and decreased 5 days postoperatively [(92.02±58.26) mg/L], both were higher than those of non-anastomotic leakage group, and the difference was statistically significant (all P<0.05, except postoperative day 2). The serum CRP level of non-anastomotic leakage group reached the peak on the second postoperative day [(83.10±37.45) mg/L] and decreased 3 days postoperatively [(48.01±27.59) mg/L]. The ROC curve was drawn with the anastomotic leakage as the state variable, and the CRP level as the detection variable. The area under the curve (AUC) at postoperative 1, 2, 4, 5, 6 and 7 days was 0.74, 0.58, 0.83, 0.82, 0.65, and 0.70, respectively. The maximum was at postoperative day 3 [0.93(95%CI: 0.86-0.99)]. The Youden index was 0.72, and the threshold of CRP was 80.09 mg/L, as the cut-off point to predict anastomotic leakage, with sensitivity, specificity, and positive predictive value of 79.3%, 92.3%, and 74.2%, respectively. CONCLUSIONS: Monitoring the postoperative serum CRP level can help predict the occurrence of anastomotic leakage after laparoscopic surgery for rectal cancer. When the serum CRP level is >80.09 mg/L on the third postoperative day, the CRP level has the largest value in predicting postoperative anastomotic leakage, and the safety of ERAS has a certain clinical significance as well.

Diagnosis and Treatment of 26 Cases of Abdominal Cocoon.

BACKGROUND AND AIMS: Abdominal cocoon (AC) is a rare abdominal disease with nonspecific clinical features, and it is difficult to be diagnosed before operation and hard to be treated in clinical practice. The aim of this study is to investigate the diagnosis and treatment of AC. METHODS: The clinical manifestations, findings during surgery, treatments, and follow-up results of 26 cases of AC were retrospectively studied from January 2001 to January 2015. RESULTS: All of 26 cases were diagnosed as AC definitely by laparotomy or laparoscopic surgery. Their clinical findings were various, with 7 intestines obstructed with bezoars and 4 intestines perforated by spiny material. Based on the existence of the second enterocoelia, all cases were categorized into 2 types: type I is absent of second enterocoelia (18 cases, 69.23%), while type II shows second enterocoelia (8 cases, 30.77%). Twenty cases (12 were type I and 8 were type II) underwent membrane excision and careful enterodialysis to release the small intestine entirely or partially, while the other 6 cases (all were type I) did not. In addition, all patients were treated with medical treatment and healthy diet and lifestyle. Finally, most of the patients recovered smoothly. CONCLUSIONS: AC can be categorized into two types; surgery is recommended for type II and part of type I with severe complications, but sometimes conservative therapy might be appropriate for type I. Laparoscopic surgery plays an important role in the diagnosis and treatment of AC. Furthermore, favorite health education, healthy diet and lifestyle are of significance in patients' recovery.

Modified FOLFOX6 With or Without Radiation Versus Fluorouracil and Leucovorin With Radiation in Neoadjuvant Treatment of Locally Advanced Rectal Cancer: Initial Results of the Chinese FOWARC Multicenter, Open-Label, Randomized Three-Arm Phase III Trial.

PURPOSE: Total mesorectal excision with fluorouracil-based preoperative chemoradiotherapy and postoperative chemotherapy is a standard treatment of locally advanced rectal cancer. This study investigated the addition of oxaliplatin with and without preoperative radiotherapy. METHODS: In this multicenter, open-label, phase III trial, we randomly assigned (1:1:1) Chinese adults (age 18 to 75 years) with locally advanced stage II/III rectal cancer to three treatments: five 2-week cycles of infusional fluorouracil (leucovorin 400 mg/m(2), fluorouracil 400 mg/m(2), and fluorouracil 2.4 g/m(2) over 48 h) plus radiotherapy (46.0 to 50.4 Gy delivered in 23 to 25 fractions during cycles 2 through 4) followed by surgery and seven cycles of infusional fluorouracil, the same treatment plus intravenous oxaliplatin 85 mg/m(2) on day 1 of each cycle (modified FOLFOX6 [mFOLFOX6]), or four to six cycles of mFOLFOX6 followed by surgery and six to eight cycles of mFOLFOX6. Random assignment was performed by using computer-generated block randomization codes. The primary end point was 3-year disease-free survival. Secondary end points of histopathologic response and toxicity are reported. RESULTS: A total of 495 patients were enrolled from June 2010 to February 2015; 475 were evaluable (fluorouracil-radiotherapy, n = 155; mFOLFOX6-radiotherapy, n = 157; mFOLFOX6, n = 163). In the fluorouracil-radiotherapy, mFOLFOX6-radiotherapy, and mFOLFOX6 groups, the rate of pathologic complete response (pCR) was 14.0%, 27.5%, and 6.6%, and downstaging (ypStage 0 to 1) was achieved by 37.1%, 56.4%, and 35.5% of patients, respectively. Higher toxicity and more postoperative complications were observed in patients who received radiotherapy. CONCLUSION: mFOLFOX6-based preoperative chemoradiotherapy results in a higher pCR rate than fluorouracil-based treatment. Perioperative mFOLFOX6 alone had inferior results and a lower pCR rate than chemoradiotherapy but led to a similar downstaging rate as fluorouracil-radiotherapy, with less toxicity and fewer postoperative complications.

Clinicopathological characteristics and long-term outcomes of colorectal cancer in elderly Chinese patients undergoing potentially curative surgery.

PURPOSE: The aim of this study was to determine the clinicopathological characteristics and outcomes of Chinese colorectal cancer (CRC) patients aged 75 years and older undergoing potentially curative surgery. METHODS: A total of 2,482 CRC patients at TNM stage I-III undergoing surgical treatment between 1995 and 2005 were evaluated, and patients were divided into a younger (<75 years old) and an elderly (≥75 years) group. RESULTS: There were 2,482 CRC patients in this study, of which 2,194 (88.4 %) patients were in the younger group (mean age 57 years) and 288 (11.6 %) were in the elderly group (mean age 79 years). Significant differences were observed between the two groups with regard to the American Society of Anesthesiologists' score, tumor location, co-morbidities, emergency procedures, use of chemotherapy, proportion admitted to the ICU, length of ICU stay, causes of death, T/N stage and postoperative recurrence. The postoperative mortality increased from 4.8 % in the younger group to 8.3 % in the older group (p = 0.011). Although significant differences were found in the overall 5-year survival (73 vs. 56 %, p < 0.0001) and disease-free 5-year survival (68 vs. 54 %, p < 0.0001) between the two groups, the cancer-specific 5-year survival was similar (88 vs. 85 %, p = 0.089) in both groups. CONCLUSIONS: Although elderly CRC patients have unique clinicopathological features, a higher postoperative mortality and a worse overall and disease-free survival compared with younger patients, the cancer-specific survival at five years is similar between elderly and younger patients. Elderly patients benefit from radical surgery and have a good postoperative oncological outcome, irrespective of their age.

Characteristics and long-term survival of colorectal cancer patients aged 44 years and younger.

BACKGROUND: This study was to investigate the clinicopathologic characteristics and prognosis of colorectal cancer (CRC) patients aged 44 years and younger. METHODS: Patients were identified from a prospectively maintained CRC database and divided into two groups by age: younger and older group (≤44 and >44 years). Clinicopathologic characteristics and postoperative outcomes were compared. RESULTS: There were 530 patients aged ≤44 years at diagnosis. More patients in the younger group had a family history of CRC compared with older patients. Younger patients were more likely than older patients to have larger tumours, infiltrative growth type tumours, poorly differentiated tumours, mucinous and signet-ring cell adenocarcinoma, and advanced TNM stages. Compared to older patients, more younger patients received chemotherapy and died of cancer-related causes. Overall survival, disease-free survival and cancer-specific survival of younger patients were comparable to older patients. Blood transfusion, TNM stage, histological grade and disease recurrence were independently associated with survival in the younger group. CONCLUSIONS: Despite younger patients having unfavourable clinicopathologic features, younger age at diagnosis of CRC appears to be associated with similar oncologic outcomes as compared to older patients.

Comparative proteomics analysis of colorectal cancer.

BACKGROUND AND OBJECTIVE: Protein expression in colon and rectal cancer (CRC) and paired normal tissues was examined by two-dimensional gel electrophoresis (2-DE) to identify differentially expressed proteins. MATERIALS AND METHODS: Five fresh colorectal cancer and paired adjacent normal tissues were obtained and differentially expressed protein spots were determined using PDQuest software, with identification on the basis of MALDI- TOF mass spectra. RESULTS: Compared with normal colorectal mucosa, protein abnormal expression of 65 spots varying more than 1.5 times were found in 2-DE gels from colorectal cancer samples (P<0.05); forty-two proteins were up-regulated and 23 were down-regulated; twelve protein spots were identified using mass spectrometry, of which 8 were up-regulated, including HSPB1 and Annexin A4, while 4 were down-regulated, the results being consistent with Western blot findings. CONCLUSIONS: Two-dimensional electrophoresis reference maps for CRC tissues and adjacent normal mucosa (NMC) were established and 12 differentially expressed proteins were identified. Up-regulated HSPB1 and Annexin A4 may play many important roles in the pathogenesis of colorectal cancer.

Screening peptides binding specifically to colorectal cancer cells from a phage random peptide library.

The aim of this study was to screen for polypeptides binding specifically to LoVo human colorectal cancer cells using a phage-displayed peptide library as a targeting vector for colorectal cancer therapy. Human normal colorectal mucous epithelial cells were applied as absorber cells for subtraction biopanning with a c7c phage display peptide library. Positive phage clones were identified by enzyme-linked immunosorbent assay and immunofluorescence detection; amino acid sequences were deduced by DNA sequencing. After 3 rounds of screening, 5 of 20 phage clones screened positive, showing specific binding to LoVo cells and a conserved RPM motif. Specific peptides against colorectal cancer cells could be obtained from a phage display peptide library and may be used as potential vectors for targeting therapy for colorectal cancer.

[Preoperative evaluation of the 64-slice spiral CT three dimensional angiography for vascular invasion in gastric cancer].

OBJECTIVE: To evaluate the preoperative diagnosis value of 64-slice spiral CT three dimensional angiography (3D CTA) for the vascular invasion in gastric cancer. METHODS: CT images of 40 patients diagnosed as gastric cancer by endoscope,who proceeded to surgical exploration from August 2006 to December 2007,were collected. These images were rebuilt by 3D CTA to judge vascular invasion by gastric cancer in comparison with the surgical finding as standard reference. RESULTS: Successful 3D CTA reconstructions were performed for all these 40 patient images. Out of 40 cases, 14 cases presented vascular invasion in the 3D CTA, and 12 of 14 cases were proved to have vascular invasion in the surgery. For assessing vascular invasion with CTA, the sensitivity was 98.1% and the specificity was 96.4% respectively (Chi Square chi(2)=0.0099,P>0.05). There was no significant differences regarding vascular invasion in gastric cancer between preoperative 3D CTA assessment and surgical finding. CONCLUSION: Sixty-four-slice spiral CT 3D angiography is effective in assessing vascular invasion in gastric cancer and is also valuable in clinical application.

[The assessment of curative effect after total mesorectal excision with autonomic nerve preservation for rectal cancer].

OBJECTIVE: To evaluate the impact on sexual function, local recurrence and survival after total mesorectal excision (TME) with autonomic nerve preservation (PANP) of rectal cancer. METHODS: One hundred and five patients after TME with PANP were followed by means of questionnaire on postoperative genital function [TME + PANP(+) group], and the results of 110 patients after TME without PANP [TME + PANP(-) group] were compared with, also their local recurrence and 5-year survival were retrospectively analyzed. RESULTS: TME + PANP(+) group was compared to TME + PANP(-) group: the erection dysfunction, 33.3% vs 63.2%; the ejaculation dysfunction, 43.8% vs 70.0% (P < 0.01), there were significant differences between two groups, but no difference in local recurrent rate and 5-year survival rate (7.6% vs 5.5%; 63.4% vs 59.7%, P > 0.05). CONCLUSION: The TME with PANP of rectal surgery ensure the radical cure of rectal cancer, at the same time reasonably save the postoperative sexual function and obtain satisfactory postoperative survival.