Hee Jin Chang

Open versus laparoscopic surgery for mid or low rectal cancer after neoadjuvant chemoradiotherapy (COREAN trial): short-term outcomes of an open-label randomised controlled trial

BACKGROUND The safety and short-term efficacy of laparoscopic surgery for rectal cancer after preoperative chemoradiotherapy has not been demonstrated. The aim of the randomised Comparison of Open versus laparoscopic surgery for mid and low REctal cancer After Neoadjuvant chemoradiotherapy (COREAN) trial was to compare open surgery with laparoscopic surgery for mid or low rectal cancer after neoadjuvant chemoradiotherapy. METHODS Between April 4, 2006, and Aug 26, 2009, patients with cT3N0-2 mid or low rectal cancer without distant metastasis after preoperative chemoradiotherapy were enrolled at three tertiary-referral hospitals. Patients were randomised 1:1 to receive either open surgery (n=170) or laparoscopic surgery (n=170), stratified according to sex and preoperative chemotherapy regimen. Short-term outcomes assessed were involvement of the circumferential resection margin, macroscopic quality of the total mesorectal excision specimen, number of harvested lymph nodes, recovery of bowel function, perioperative morbidity, postoperative pain, and quality of life. Analyses were based on the intention-to-treat population. Patients continue to be followed up for the primary outcome (3-year disease-free survival). This study is registered with ClinicalTrials.gov, number NCT00470951. FINDINGS Two patients (1.2%) in the laparoscopic group were converted to open surgery, but were included in the laparoscopic group for analyses. Estimated blood loss was less in the laparoscopic group than in the open group (median 217.5 mL [150.0-400.0] in the open group vs 200.0 mL [100.0-300.0] in the laparoscopic group, p=0.006), although surgery time was longer in the laparoscopic group (mean 244.9 min [SD 75.4] vs 197.0 min [62.9], p<0.0001). Involvement of the circumferential resection margin, macroscopic quality of the total mesorectal excision specimen, number of harvested lymph nodes, and perioperative morbidity did not differ between the two groups. The laparoscopic surgery group showed earlier recovery of bowel function than the open surgery group (time to pass first flatus, median 38.5 h [23.0-53.0] vs 60.0 h [43.0-73.0], p<0.0001; time to resume a normal diet, 85.0 h [66.0-95.0] vs 93.0 h [86.0-121.0], p<0.0001; time to first defecation, 96.5 h [70.0-125.0] vs 123 h [94.0-156.0], p<0.0001). The total amount of morphine used was less in the laparoscopic group than in the open group (median 107.2 mg [80.0-150.0] vs 156.9 mg [117.0-185.2], p<0.0001). 3 months after proctectomy or ileostomy takedown, the laparoscopic group showed better physical functioning score than the open group (0.501 [n=122] vs -4.970 [n=128], p=0.0073), less fatigue (-5.659 [n=122] vs 0.098 [n=129], p=0.0206), and fewer micturition (-2.583 [n=122] vs 4.725 [n=129], p=0.0002), gastrointestinal (-0.400 [n=122] vs 4.331 [n=129], p=0.0102), and defecation problems (0.535 [n=103] vs 5.327 [n=99], p=0.0184) in repeated measures analysis of covariance, adjusted for baseline values. INTERPRETATION Laparoscopic surgery after preoperative chemoradiotherapy for mid or low rectal cancer is safe and has short-term benefits compared with open surgery; the quality of oncological resection was equivalent.

Open versus laparoscopic surgery for mid-rectal or low-rectal cancer after neoadjuvant chemoradiotherapy (COREAN trial): survival outcomes of an open-label, non-inferiority, randomised controlled trial

BACKGROUND Compared with open resection, laparoscopic resection of rectal cancers is associated with improved short-term outcomes, but high-level evidence showing similar long-term outcomes is scarce. We aimed to compare survival outcomes of laparoscopic surgery with open surgery for patients with mid-rectal or low-rectal cancer. METHODS The Comparison of Open versus laparoscopic surgery for mid or low REctal cancer After Neoadjuvant chemoradiotherapy (COREAN) trial was an open-label, non-inferiority, randomised controlled trial done between April 4, 2006, and Aug 26, 2009, at three centres in Korea. Patients (aged 18-80 years) with cT3N0-2M0 mid-rectal or low-rectal cancer who had received preoperative chemoradiotherapy were randomly assigned (1:1) to receive either open or laparoscopic surgery. Randomisation was stratified by sex and preoperative chemotherapy regimen. Investigators were masked to the randomisation sequence; patients and clinicians were not masked to the treatment assignments. The primary endpoint was 3 year disease-free survival, with a non-inferiority margin of 15%. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00470951. FINDINGS We randomly assigned 340 patients to receive either open surgery (n=170) or laparoscopic surgery (n=170). 3 year disease-free survival was 72·5% (95% CI 65·0-78·6) for the open surgery group and 79·2% (72·3-84·6) for the laparoscopic surgery group, with a difference that was lower than the prespecified non-inferiority margin (-6·7%, 95% CI -15·8 to 2·4; p<0·0001). 25 (15%) patients died in the open group and 20 (12%) died in the laparoscopic group. No deaths were treatment related. INTERPRETATION Our results show that laparoscopic resection for locally advanced rectal cancer after preoperative chemoradiotherapy provides similar outcomes for disease-free survival as open resection, thus justifying its use. FUNDING National Cancer Center, South Korea.

Assessment of lymph node metastases using 18F-FDG PET in patients with advanced gastric cancer

PurposeThe aim of this study was to assess the diagnostic accuracy of 18F-fluoro-2-deoxyglucose (FDG) positron emission tomography (PET) with respect to lymph node (LN) metastasis in patients with advanced gastric cancer, and to ascertain the factors that affect this accuracy.MethodsSeventy-three patients with advanced gastric cancer, verified in all cases by endoscopic biopsy, were enrolled in this prospective study. We conducted FDG PET and other routine preoperative studies, including abdominal computed tomography (CT). Patients underwent either curative-intent gastrectomy and lymphadenectomy (n=67) or exploratory laparotomy. The Japanese system for the classification of gastric cancer was used for LN assessment.ResultsFDG PET was able to detect primary lesions in 70 of the 73 cases. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value of FDG PET for LN metastasis were 40%, 95%, 91% and 56%, respectively. Signet-ring cell carcinoma was associated with the lowest sensitivity (15%), whereas other cell types could be detected with moderate sensitivity (30–71%) and high specificity (93–100%). According to multiple logistic regression, the standardised uptake value for primary tumours was the only independent variable to be significantly related to sensitivity for LN metastasis (p=0.02, odds ratio=1.14). CT was superior to PET in terms of sensitivity (p<0.0001), and PET was superior to CT in terms of specificity (p<0.0001) and PPV (p=0.05).ConclusionFDG PET exhibits good specificity for LN staging of gastric cancer, and FDG uptake in the primary tumour is significantly related to the accuracy of FDG PET. Despite some clear limitations, FDG PET proved useful in the LN staging of FDG-avid gastric cancer.

Down-regulation of Mitochondrial F1F0-ATP Synthase in Human Colon Cancer Cells with Induced 5-Fluorouracil Resistance

5-Fluorouracil (5-FU) is widely used for treatment of advanced colorectal cancer. However, it is common for such patients to develop resistance to 5-FU, and this drug resistance becomes a critical problem for chemotherapy. The mechanisms underlying this resistance are largely unknown. To screen for proteins possibly responsible for 5-FU resistance, cells resistant to 5-FU were derived from human colon cancer cell lines and two-dimensional gel electrophoresis–based comparative proteomics was done. Two-dimensional gel electrophoresis data showed there was lower expression of the α subunit of mitochondrial F1F0-ATP synthase (ATP synthase) in 5-FU–resistant cells compared with parent cells. Western blotting showed that expression of other ATP synthase complex subunits was also lower in 5-FU–resistant cell lines and that these resistant cells also showed decreased ATP synthase activity and reduced intracellular ATP content. The ATP synthase inhibitor, oligomycin A, strongly antagonized 5-FU–induced suppression of cell proliferation. When 5-FU sensitivity was compared with ATP synthase activity in six different human colon cancer cell lines, a positive correlation has been found. Furthermore, suppressed ATP synthase d-subunit expression by siRNA transfection increased cell viability in the presence of 5-FU. Bioenergetic dysfunction of mitochondria has been reported as a hallmark of many types of cancers (i.e., down-regulation of ATP synthase β-subunit expression in liver, kidney, colon, squamous oesophageal, and lung carcinomas, as well as in breast and gastric adenocarcinomas). Our findings show that ATP synthase down-regulation may not only be a bioenergetic signature of colorectal carcinomas but may also lead to cellular events responsible for 5-FU resistance.

Pathologic complete response of primary tumor following preoperative chemoradiotherapy for locally advanced rectal cancer: long-term outcomes and prognostic significance of pathologic nodal status (KROG 09-01).

Objective: To investigate long-term outcomes of locally advanced rectal cancer (LARC) patients with postchemoradiotherapy (post-CRT) pathologic complete response of primary tumor (ypT0) and determine prognostic significance of post-CRT pathologic nodal (ypN) status. Background: LARC patients with post-CRT pathologic complete response were suggested to have favorable long-term outcomes, but prognostic significance of ypN status has never been specifically defined in ypT0 patients. Methods: The Korean Radiation Oncology Group collected clinical data for 333 LARC patients with ypT0 following preoperative CRT and curative radical resections between 1993 and 2007. Sphincter preservation surgery and abdominoperineal resection were performed in 283 (85.0%) and 50 (15.0%) patients, respectively. Postoperative chemotherapy was given to 285 (85.6%) patients. Survival was estimated by the Kaplan-Meier method, and the Cox proportional hazard model was used in multivariate analyses. Results: After median follow-up of 43 (range = 14–172) months, 5-year disease-free survival (DFS) was 84.6% and overall survival (OS) was 92.8%. The ypN status was ypT0N0 in 304 (91.3%), ypT0N1 in 22 (6.6%), and ypT0N2 in 7 (2.1%) patients. The ypN status was the most relevant independent prognostic factor for both DFS and OS in ypT0 patients. The 5-year DFS and OS was 88.5% and 94.8% in ypT0N0 patients, and 45.2% and 72.8% in ypT0N+ patients (both, P < 0.001). Conclusions: LARC patients achieving ypT0N0 after preoperative CRT had favorable long-term outcomes, whereas positive ypN status had a poor prognosis even after total regression of primary tumor.

Optimal surgery time after preoperative chemoradiotherapy for locally advanced rectal cancers.

Objective:To evaluate the effect of the time interval between chemoradiotherapy (CRT) and surgery on CRT response and surgical outcomes. Summary Background Data:Although preoperative CRT is a standard component of multimodal treatment for locally advanced rectal cancers, the optimal time for surgery after CRT has yet to be established. This study analyzed outcomes in 397 prospectively enrolled patients with locally advanced rectal cancer who underwent fractionated CRT involving 50.4 Gy radiotherapy followed by surgical resection between 4 and 8 weeks later. Methods:Patients were divided into 2 groups according to the time that elapsed between CRT and surgery: group A (28–41 day interval) and group B (42–56 day interval). CRT responses and surgical outcomes were analyzed. Results:Of the 397 patients, 217 (54.7%) were in group A and 180 (45.3%) in group B. The 2 groups were similar in terms of pretreatment characteristics other than a slight difference in mean age (A: 55.3 years vs. B: 57.5 years, P = 0.042). Analysis of CRT responses showed that the 2 groups were similar in terms of T-level downstaging rate (A: 47.5% vs. B: 44.4%, P = 0.548), volume reduction rate (A: 34.6% vs. B: 34.2%, P = 0.870) and complete response rate (A: 13.8% vs. B: 15.0%, P = 0.740). Analysis of surgical outcomes showed that the 2 groups were also similar in terms of sphincter-preservation rate (A: 83.9% vs. B: 82.2%, P = 0.688) and anastomosis-related complication rate (A: 5.5% vs. B: 3.9%, P = 0.453). The median follow-up period was 31 months (range, 5–63), and both groups showed similar local recurrence-free survival rates (P = 0.1165). Conclusion:The present findings suggest that compared with a 4 to 6 week interval, delaying surgery for 6 to 8 weeks after completion of fractionated radiotherapy with concurrent chemotherapy does not improve CRT response or the sphincter-preservation rate, and does not decrease morbidity or local recurrence.

Influence of preoperative chemoradiotherapy on the number of lymph nodes retrieved in rectal cancer.

Objective:To evaluate the relation of preoperative chemoradiotherapy to the number of lymph nodes retrieved in curative intent surgery for rectal cancer. Summary Background Data:Current guidelines recommend evaluation of least 12 to 14 lymph nodes in rectal cancer. It is well known that lymph nodes retrieval is affected by many factors. Methods:This was a retrospective study of 615 patients who underwent curative intent surgery for primary rectal cancer. Preoperative chemoradiotherapy involving 50.4 Gy fractionated radiotherapy and concurrent chemotherapy was performed in patients with locally advanced rectal cancer (clinically T3 or T4). We explored associations between the number of lymph nodes retrieved in the pathologic specimen and patient demographics (age, gender, body mass index [BMI]), treatment (surgeon, sphincter-saving, preoperative chemoradiotherapy), and tumor-related variables (location, stage, histology). After adjustment for other factors, we compared the mean number of obtained lymph nodes between patients treated with preoperative chemoradiotherapy and those treated without preoperative chemoradiotherapy. Results:Univariate analysis demonstrated that age, BMI, preoperative chemoradiotherapy, location, and stage significantly related the number of lymph nodes retrieved. Multivariate analysis revealed age, BMI, preoperative chemoradiotherapy, and stage as independent factors influencing the number of lymph nodes retrieved. The mean number of lymph nodes adjusted for age, BMI, and stage was significantly lower in patients treated with preoperative chemoradiotherapy than in those treated without preoperative chemoradiotherapy (14.5 vs. 21.5, P < 0.001). The reduction rate by preoperative chemoradiotherapy was 32.6% (7/21.5). In patients who underwent preoperative chemoradiotherapy, advanced age (P < 0.001) and high BMI (P = 0.037) were associated with decreased number of retrieved lymph nodes. Conclusions:Preoperative chemoradiotherapy significantly decreased the number of retrieved lymph nodes by approximately 33%. Therefore, the recommended number of retrieved lymph nodes should be adjusted when rectal cancer is treated with preoperative chemoradiotherapy.

Metabotropic Glutamate Receptor 4 Expression in Colorectal Carcinoma and Its Prognostic Significance

Purpose: Metabotropic glutamate receptors (mGluR) play a variety of roles in both neuronal and nonneuronal cells. Recently, we reported that mGluR4 mediates 5-fluorouracil resistance in a human colon cancer cell line. In this study, we evaluated the nonneural expression of mGluR4 and clarified the existence of mGluR4 in normal colon epithelium and colorectal carcinomas. We also investigated the association of mGluR4 expression levels with various clinicopathologic parameters. Experimental Design: mGluR4 expression was investigated in 21 normal and 312 malignant tissues from various organs using immunohistochemistry. In addition, 241 cases of colorectal carcinomas were examined and correlations between mGluR4 expression and various clinicopathologic parameters were then statistically analyzed. Results: Expression of mGluR4 was identified in the normal epithelia of the upper respiratory tract, gastrointestinal tracts, breast, uterine cervix, urinary bladder, and skin, whereas it was not detected in the thyroid, lung alveoli, liver, testis, or prostate. In the corresponding malignant tissues, mGluR4 expression was frequently identified in colorectal carcinoma (68%), followed by malignant melanoma, laryngeal carcinoma, and breast carcinomas. Expression of mGluR4 was detected in 131 (54%) of 241 colorectal carcinomas and 12 (5%) cases among them showed overexpression in their cytoplasms. Loss of mGluR4 expression was negatively associated with tumor differentiation (P = 0.028), whereas overexpression of mGluR4 was positively associated with recurrence (P = 0.034) and poor disease-free survival (P = 0.017) in multivariate analyses. Conclusions: Our results suggest that mGluR4 signaling may play a role in colorectal carcinomas and that overexpression of mGluR4 is associated with poor prognosis.

Notch1 counteracts WNT/β-catenin signaling through chromatin modification in colorectal cancer

Crosstalk between the Notch and wingless-type MMTV integration site (WNT) signaling pathways has been investigated for many developmental processes. However, this negative correlation between Notch and WNT/β-catenin signaling activity has been studied primarily in normal developmental and physiological processes in which negative feedback loops for both signaling pathways are intact. We found that Notch1 signaling retained the capability of suppressing the expression of WNT target genes in colorectal cancers even when β-catenin destruction by the adenomatous polyposis coli (APC) complex was disabled. Activation of Notch1 converted high-grade adenoma into low-grade adenoma in an Apcmin mouse colon cancer model and suppressed the expression of WNT target genes in human colorectal cancer cells through epigenetic modification recruiting histone methyltransferase SET domain bifurcated 1 (SETDB1). Extensive microarray analysis of human colorectal cancers also showed a negative correlation between the Notch1 target gene, Notch-regulated ankyrin repeat protein 1 (NRARP), and WNT target genes. Notch is known to be a strong promoter of tumor initiation, but here we uncovered an unexpected suppressive role of Notch1 on WNT/β-catenin target genes involved in colorectal cancer.

Pathologic Nodal Classification Is the Most Discriminating Prognostic Factor for Disease-Free Survival in Rectal Cancer Patients Treated With Preoperative Chemoradiotherapy and Curative Resection

PURPOSE We retrospectively evaluated the effects of clinical and pathologic factors on disease-free survival (DFS) with the aim of identifying the most discriminating factor predicting DFS in rectal cancer patients treated with preoperative chemoradiotherapy (CRT) and curative resection. METHODS AND MATERIALS The study involved 420 patients who underwent preoperative CRT and curative resection between August 2001 and October 2006. Gender, age, distance from the anal verge, histologic type, histologic grade, pretreatment carcinoembryonic antigen (CEA) level, cT, cN, cStage, circumferential resection margin, type of surgery, preoperative chemotherapy, adjuvant chemotherapy, ypT, ypN, ypStage, and tumor regression grade (TRG) were analyzed to identify prognostic factors associated with DFS. To compare the discriminatory prognostic ability of four tumor response-related pathologic factors (ypT, ypN, ypStage, and TRG), the Akaike information criteria were calculated. RESULTS The 5-year DFS rate was 75.4%. On univariate analysis, distance from the anal verge, histologic type, histologic grade, pretreatment CEA level, cT, circumferential resection margin, type of surgery, preoperative chemotherapeutic regimen, ypT, ypN, ypStage, and TRG were significantly associated with DFS. Multivariate analysis showed that the four parameters ypT, ypN, ypStage, and TRG were, consistently, significant prognostic factors for DFS. The ypN showed the lowest Akaike information criteria value for DFS, followed by ypStage, ypT, and TRG, in that order. CONCLUSION In our study, ypT, ypN, ypStage, and TRG were important prognostic factors for DFS, and ypN was the most discriminating factor.