Chang Sik Yu

Oxaliplatin, fluorouracil, and leucovorin versus fluorouracil and leucovorin as adjuvant chemotherapy for locally advanced rectal cancer after preoperative chemoradiotherapy (ADORE): an open-label, multicentre, phase 2, randomised controlled trial.

BACKGROUND The role of adjuvant chemotherapy for patients with rectal cancer is controversial, especially when used after preoperative chemoradiotherapy. Fluoropyrimidine-based adjuvant chemotherapy, including fluorouracil and leucovorin, has been widely used; however, the addition of oxaliplatin to fluorouracil and leucovorin (FOLFOX), a standard adjuvant regimen for colon cancer, has not been tested in rectal cancer. We aimed to compare the efficacy and safety of adjuvant fluorouracil and leucovorin with that of FOLFOX in patients with locally advanced rectal cancer after preoperative chemoradiotherapy. METHODS In this open-label, multicentre, phase 2, randomised trial, patients with postoperative pathological stage II (ypT3-4N0) or III (ypTanyN1-2) rectal cancer after preoperative fluoropyrimidine-based chemoradiotherapy and total mesorectal excision were recruited and randomly assigned (1:1) via a web-based software platform to receive adjuvant chemotherapy with either four cycles of fluorouracil and leucovorin (fluorouracil 380 mg/m(2) and leucovorin 20 mg/m(2) on days 1-5, every 4 weeks) or eight cycles of FOLFOX (oxaliplatin 85 mg/m(2), leucovorin 200 mg/m(2), and fluorouracil bolus 400 mg/m(2) on day 1, and fluorouracil infusion 2400 mg/m(2) for 46 h, every 2 weeks). Stratification factors were pathological stage (II vs III) and centre. Neither patients nor investigators were masked to group assignment. The primary endpoint was 3-year disease-free survival, analysed by intention to treat. This study is fully enrolled, is in long-term follow-up, and is registered with ClinicalTrials.gov, number NCT00807911. FINDINGS Between Nov 19, 2008, and June 12, 2012, 321 patients were randomly assigned to fluorouracil and leucovorin (n=161) and FOLFOX (n=160). 141 (95%) of 149 patients in the fluorouracil plus leucovorin group and 141 (97%) of 146 in the FOLFOX group completed all planned cycles of adjuvant treatment. Median follow-up was 38·2 months (IQR 26·4-50·6). 3-year disease-free survival was 71·6% (95% CI 64·6-78·6) in the FOLFOX group and 62·9% (55·4-70·4) in the fluorouracil plus leucovorin group (hazard ratio 0·657, 95% CI 0·434-0·994; p=0·047). Any grade neutropenia, thrombocytopenia, fatigue, nausea, and sensory neuropathy were significantly more common in the FOLFOX group than in the fluorouracil plus leucovorin group; however, we noted no significant difference in the frequency of these events at grade 3 or 4. The most common grade 3 or worse adverse events were neutropenia (38 [26%] of 149 patients in the fluorouracil plus leucovorin group vs 52 [36%] of 146 patients in the FOLFOX group), leucopenia (eight [5%] vs 12 [8%]), febrile neutropenia (four [3%] vs one [<1%]), diarrhoea (four [3%] vs two [1%]), and nausea (one [<1%] vs two [1%]). INTERPRETATION Adjuvant FOLFOX improves disease-free survival compared with fluorouracil plus leucovorin in patients with locally advanced rectal cancer after preoperative chemoradiotherapy and total mesorectal excision, and warrants further investigation. FUNDING Korea Healthcare Technology R&D Project (South Korean Ministry of Health and Welfare).

Risk Factors and Oncologic Impact of Anastomotic Leakage after Rectal Cancer Surgery

PurposeThe impact of anastomotic leakage on the long-term oncologic outcome is not clear. This retrospective study evaluated risk factors and oncologic impacts of anastomotic leakage after rectal cancer surgery.MethodsData were analyzed from 1,391 patients who underwent sphincter preservation for rectal cancer between January 1997 and August 2003. Operations were classified as anterior resection (n = 164), low anterior resection (n = 898), or ultralow anterior resection (n = 329).ResultsThe anastomotic leakage rate was 2.5 percent. Multivariate analysis identified male (hazard ratio, 3.03), old age (hazard ratio, 2.42), and lower anastomosis level (hazard ratio, 2.68) as risk factors for leakage. The local recurrence rates were 9.6 and 2.2 percent for the leakage and nonleakage groups, respectively but were not significant (P = 0.14). The overall five-year survival rates were 55.1 and 74.1 percent in the leakage and nonleakage groups, respectively (P < 0.05), and the cancer-specific survival rates were 63 and 78.3 percent in the leakage and nonleakage groups, respectively (P = 0.05). However, in subgroup analysis, significant differences were identified only in Stage III patients.ConclusionsAge, sex, and ultralow anterior resection were found to be risk factors for anastomotic leakage after rectal cancer surgery. In addition, leakage was associated with poor survival.

Autologous adipose tissue-derived stem cells for the treatment of Crohn's fistula: a phase I clinical study.

The present study was designed to evaluate the safety and potential of adipose tissue-derived stem cells (ASCs) for the treatment of Crohns fistula. In this dose escalation study, patients were sequentially enrolled into three dosing groups with at least three patients per group. The first three patients (group 1) were given 1 × 107 cells/ml. After 4 weeks, this dose was deemed safe, and so an additional four patients (group 2) were given 2 × 107 cells/ml. Four weeks later, after which this second dose was deemed safe, a third and final group of three patients were given 4 × 107 cells/ml. Each patient was followed for a minimum of 8 weeks. Patients who showed complete healing at week 8 were followed up for an additional 6 months. Efficacy endpoint was complete healing at week 8 after injection, defined as complete closure of the fistula track and internal and external openings without drainage or signs of inflammation. There were no grade 3 or 4 severity adverse events, and there were no adverse events related to the study drug. Two patients in group 2, treated with 2 × 107 ASCs/ml, showed complete healing at week 8 after injection. Of the three patients enrolled in group 3, treated with 4 × 107 ASCs/ml, one showed complete healing. Outcome in another patient was assessed as partial healing due to incomplete closure of the external opening, although the inside of fistula track was filled considerably and there was no drainage. All three patients with complete healing at week 8 showed a sustained effect without recurrence 8 months after injection. In conclusion, this study demonstrates the tolerability, safety, and potential efficacy of ASCs for the treatment of Crohns fistula and provides support for further clinical study.

Clinical features and long-term prognosis of Crohn's disease in Korea

Abstract Objective. Recent studies have suggested that the clinical characteristics and genetic background of Crohns disease (CD) patients differ between Asian and Caucasian individuals. However, the clinical features and course of CD in Asian patients remain unclear. Therefore, we investigated the clinical features and long-term prognosis of CD in a Korean population. Material and methods. We retrospectively analyzed 278 Korean patients with CD first diagnosed at the Asan Medical Center between March 1991 and February 2007. Results. The male-to-female ratio was 2.2:1 and the median age at diagnosis was 23 years. The median duration of follow-up was 71 months (range, 1–210 months). At diagnosis, 187 patients (67.3%) had disease in both small bowel and colon, 68 (24.4%) had isolated small bowel disease, and 23 (8.3%) had isolated colonic disease. The number of patients with stricturing or penetrating behavior as defined by the Montreal classification increased from 87 (31.3%) at diagnosis to 141 (50.7%) at final evaluation. One hundred and thirty patients (46.8%) experienced perianal fistulas before and/or after diagnosis of CD. A total of 71 patients (25.5%) underwent intestinal resection and the cumulative probability of intestinal resection after 1, 5, and 10 years was 15.5%, 25.0%, and 32.8%, respectively. Conclusions. Korean CD patients differed from Western patients in gender distribution, disease location, and perianal fistula occurrence. Korean CD patients may also have better clinical courses than Western patients, as indicated by the lower intestinal resection rate.

Randomized phase 3 trial comparing preoperative and postoperative chemoradiotherapy with capecitabine for locally advanced rectal cancer

Although many trials have shown the efficacy of preoperative chemoradiotherapy (CRT) or postoperative CRT compared with surgery alone, the optimal sequence of radiotherapy and surgery is unclear. The authors reported the final results of this single institution prospective randomized phase 3 trial comparing preoperative CRT with postoperative CRT using capecitabine in survival, local control, sphincter preservation, and toxicity for the treatment of locally advanced rectal cancer.

Comparative analysis of radiofrequency ablation and surgical resection for colorectal liver metastases

Purpose To evaluate the comparative therapeutic efficacy of radiofrequency ablation (RFA) and hepatic resection for the treatment of colorectal liver metastasis (CRLM). Methods Between 1996 and 2008, 177 patients underwent RFA, 278 underwent hepatic resection and 27 underwent combination therapy for CRLM. Comparative analysis of clinical outcomes was performed including number of liver metastases, tumor size, and time of CRLM. Results Based on multivariate analysis, overall survival (OS) correlated with the number of liver metastases and the use of combined chemotherapy (P < 0.001, respectively). Disease-free survival (DFS) also correlated with the number of liver metastases (P < 0.001). In the 226 patients with solitary CRLM < 3 cm, OS and DFS rates did not differ between the RFA group and the resection group (P = 0.962 and P = 0.980). In the 70 patients with solitary CRLM ≥ 3 cm, DFS was significantly lower in the RFA group as compared with the resection group (P = 0.015). Conclusion The results indicate that RFA may be a safe alternative treatment for solitary CRLM less than 3 cm, with outcomes equivalent to those achieved with hepatic resection. A randomized controlled study comparing RFA and resection for patients with single small metastasis would help to determine the most efficient treatment modalities for CRLM.

Long-term Prognosis of Crohn's Disease and Its Temporal Change Between 1981 and 2012: A Hospital-based Cohort Study from Korea

Background:To date, no large-scale studies have evaluated the prognosis of Crohns disease (CD) over a period of 3 decades in non-Caucasian populations. The aims of this study were to update the current information on the long-term prognosis of CD using a large series of patients and to evaluate changes in treatment paradigms over time and their impact on the prognosis of CD in Korea. Methods:We retrospectively analyzed 2043 Korean patients with CD who visited the Asan Medical Center. The study subjects were divided into 3 groups according to the year of diagnosis (cohort 1: 1981–2000, cohort 2: 2001–2005, and cohort 3: 2006–2012). Results:Azathioprine/6-mercaptopurine and anti–tumor necrosis factor agents have been used increasingly more frequently and earlier over the past 30 years, with a 5-year cumulative probability of prescription of 28.9% and 1.4%, respectively, in cohort 1 and 88.1% and 23.7%, respectively, in cohort 3 (P < 0.001). A total of 726 patients (35.5%) underwent intestinal resection, with a cumulative probability of intestinal resection 10, 20, and 30 years after diagnosis of 43.5%, 70.0%, and 76.1%, respectively. The cumulative probability of surgery was significantly lower in cohort 3 than in cohort 1 (P = 0.012). Early use of azathioprine/6-mercaptopurine was significantly associated with delayed need for intestinal resection by multivariate Cox analysis (hazard ratio: 0.63, 95% confidence interval: 0.46–0.85). Conclusions:Korean patients with CD may have a similar clinical course to Westerners, as indicated by the intestinal resection rate. The surgery rate has decreased over time, and early use of azathioprine/6-mercaptopurine was related to its decrease.

CpG island methylation as an early event during adenoma progression in carcinogenesis of sporadic colorectal cancer

Background and Aims:  CpG island methylation is present in various tumors, including colorectal carcinomas, and is thought to be an important mechanism in carcinogenesis. We evaluated the methylation status of primary colorectal tumors to determine its role in the adenoma to carcinoma sequence.

Incremental Value of Liver MR Imaging in Patients with Potentially Curable Colorectal Hepatic Metastasis Detected at CT: A Prospective Comparison of Diffusion-weighted Imaging, Gadoxetic Acid–enhanced MR Imaging, and a Combination of Both MR Techniques

PURPOSE To prospectively compare diagnostic performance of diffusion-weighted (DW) imaging, gadoxetic acid-enhanced magnetic resonance (MR) imaging, both techniques combined (combined MR imaging), and computed tomography (CT) for detecting colorectal hepatic metastases and evaluate incremental value of MR for patients with potentially curable colorectal hepatic metastases detected with CT. MATERIALS AND METHODS In this institutional review board-approved prospective study, with informed consent, 51 patients (39 men, 12 women; mean age, 62 years) with potentially resectable hepatic metastases detected with CT underwent liver MR, including DW imaging and gadoxetic acid-enhanced MR. Two independent readers reviewed DW, gadoxetic acid-enhanced, combined MR, and CT image sets to detect hepatic metastases. The figure-of-merit (FOM) value representing overall diagnostic performance, sensitivity, and positive predictive value (PPV) for each image set were analyzed by using free-response receiver operating characteristic analysis and generalized estimating equations. RESULTS There were 104 hepatic metastases in 47 patients. The pooled FOM values, sensitivities, and PPVs of combined MR (FOM value, 0.93; sensitivity, 98%; and PPV, 88%) and gadoxetic acid-enhanced MR (FOM value, 0.92; sensitivity, 95%; and PPV, 90%) were significantly higher than those of CT (FOM value, 0.82; sensitivity, 85%; and PPV, 73%) (P < .006). The pooled FOM value and sensitivity of combined MR (FOM value, 0.92; sensitivity, 95%) was also significantly higher than that of DW imaging (FOM value, 0.82; sensitivity, 79%) for metastases (≤1-cm diameter) (P ≤ .003). DW imaging showed significantly higher pooled sensitivity (79%) and PPV (60%) than CT (sensitivity, 50%; PPV, 33%) for the metastases (≤1-cm diameter) (P ≤ .004). In 47 patients with hepatic metastases, combined MR depicted more metastases than CT in 10 and 14 patients, respectively, according to both readers. CONCLUSION Gadoxetic acid-enhanced MR and combined MR are more accurate than CT in detecting colorectal hepatic metastases, have an incremental value when added to CT alone for detecting additional metastases, and can be routinely performed in patients with potentially curable hepatic metastases detected with CT.

Malignant rectal obstruction within 5 cm of the anal verge: is there a role for expandable metallic stent placement?

BACKGROUND Placement of expandable metallic stents (EMS) has been considered contraindicated for patients with malignant rectal obstruction within 5 cm of the anal verge because of the potential problems of anal pain. OBJECTIVE Our purpose was to investigate the technical feasibility, clinical effectiveness, and safety of EMS placement in patients with malignant rectal obstruction within 5 cm of the anal verge. DESIGN Retrospective study. SETTING Single tertiary referral university hospital. PATIENTS The sites of obstruction included the rectum within 5 cm (range, 25-50 mm) of the anal verge in 16 patients (group A) and more than 5 cm (range, 53-74 mm) in 14 patients (group B). INTERVENTIONS Placement of 3 types of EMS. MAIN OUTCOME MEASUREMENTS Complications including pain were evaluated and compared between 2 groups with the Fisher exact test. RESULTS The overall technical success rate was 100%. Colon perforation occurred in 2 patients, who underwent emergency surgery. Ten (62.5%) of group A and 1 (7.1%) of group B complained of pain (P = .011). In 3 of the 10 patients in group A, the pain disappeared spontaneously within a week or was tolerated by the patients without use of analgesics, although the remaining 7 patients of group A and the 1 patient in group B needed analgesics until death or elective surgery. LIMITATIONS Retrospective study. CONCLUSIONS Placement of EMS in patients with malignant rectal obstruction within 5 cm of the anal verge seems feasible and relatively safe and may provide adequate palliation and preoperative decompression of obstruction symptoms. Anal pain was tolerable to the patients with or without use of analgesics.