How to reduce anastomotic leakage in colorectal surgery-report from German expert meeting.

AIMS: Anastomotic leakage is one of the most worrisome complications in colorectal surgery. An expert meeting was organized to discuss and find a consensus on various aspects of the surgical management of colorectal disease with a possible impact on anastomotic leakage. METHODS: A three-step Delphi-method was used to find consensus recommendations. RESULTS: Strong consensus was achieved for the use of mechanical bowel preparation and oral antibiotics prior to colorectal resections, the abundance of non-selective NSAIDs, the preoperative treatment of severe iron deficiency anemia, and for attempting to improve the patients' general performance in the case of frailty. Concerning technical aspects of rectal resection, there was a strong consensus in regard to routinely mobilizing the splenic flexure, to dividing the inferior mesenteric vein, and to using air leak tests to check anastomotic integrity. There was also a strong consensus on not to oversew the stapled anastomoses routinely, to use protective ileostomies for low rectal and intersphincteric, but not for high-rectal anastomoses. Furthermore, a consensus was reached in regard to using CT-scans with rectal contrast enema to evaluate suspected anastomotic leakage as well as measuring C-reactive protein routinely to monitor the postoperative course after colorectal resections. No consensus was found concerning the indication and technique for testing bowel perfusion, the routine use of endoscopy to check the integrity of the anastomosis, the placement of transanal drains for rectal anastomoses and the management of anastomotic leakage with peritonitis. CONCLUSION: Consensus could be found for several practice details in the perioperative management in colorectal surgery that might have an influence on anastomotic leakage.

CoCStom trial: study protocol for a randomised trial comparing completeness of adjuvant chemotherapy after early versus late diverting stoma closure in low anterior resection for rectal cancer.

BACKGROUND: Current evidence supports a diverting stoma in patients undergoing low anterior resection with total mesorectal excision for rectal cancer as it reduces clinical severity of anastomotic leakage. However, relevant stoma morbidity after rectal cancer surgery exists and has a significant impact on quality of life. Moreover, a diverting stoma has an influence on completeness of chemotherapy but it remains unclear in which way. There is no evidence regarding optimal timing for stoma closure in relation to adjuvant chemotherapy. Two randomised controlled trials have studied early stoma closure after low anterior resection in patients with rectal cancer, one of them showing that early closure around day 8 after resection is possible without increasing morbidity. METHODS/DESIGN: CoCStom is a randomised multicentre trial comparing completeness of adjuvant chemotherapy as primary endpoint after early (8-10 days after resection, before starting adjuvant therapy) versus late (~26 weeks after resection and completion of adjuvant therapy) stoma closure in patients with locally advanced rectal cancer undergoing low anterior resection after neoadjuvant therapy. After exclusion of post-operative anastomotic leakage 257 patients from 30 German hospitals are planned to be included in order to assure a power of 80% for the confirmatory analysis of at least 214 evaluable cases. An absolute increase of 20% for the rate of completely administered adjuvant chemotherapy is regarded as a clinically meaningful step forward and serves as basis for sample size calculation. Quality of life, stoma-related complications, individual completeness of chemotherapy rate, percentage of patients stopping adjuvant therapy or undergoing dose modifications or delay, oncological outcomes, cumulative days of hospitalisation and number of readmissions, rate of symptomatic anastomotic leaks after stoma closure, mortality, post-operative complications and toxicity of adjuvant chemotherapy are secondary endpoints. DISCUSSION: The CoCStom trial aims to clarify optimal timing of stoma closure in the context of adjuvant chemotherapy. Depending on the results of the trial, patients could benefit either from early or late stoma closure in regard to long term oncological survival due to a higher rate of completeness of adjuvant chemotherapy treatment and thus better effectiveness. TRIAL REGISTRATION: German Clinical Trials Register, DRKS00005113. Registered 28 August 2013.

Chemoradiotherapy with capecitabine versus fluorouracil for locally advanced rectal cancer: a randomised, multicentre, non-inferiority, phase 3 trial.

BACKGROUND: Fluorouracil-based chemoradiotherapy is regarded as a standard perioperative treatment in locally advanced rectal cancer. We investigated the efficacy and safety of substituting fluorouracil with the oral prodrug capecitabine. METHODS: This randomised, open-label, multicentre, non-inferiority, phase 3 trial began in March, 2002, as an adjuvant trial comparing capecitabine-based chemoradiotherapy with fluorouracil-based chemoradiotherapy, in patients aged 18 years or older with pathological stage II-III locally advanced rectal cancer from 35 German institutions. Patients in the capecitabine group were scheduled to receive two cycles of capecitabine (2500 mg/m(2) days 1-14, repeated day 22), followed by chemoradiotherapy (50·4 Gy plus capecitabine 1650 mg/m(2) days 1-38), then three cycles of capecitabine. Patients in the fluorouracil group received two cycles of bolus fluorouracil (500 mg/m(2) days 1-5, repeated day 29), followed by chemoradiotherapy (50·4 Gy plus infusional fluorouracil 225 mg/m(2) daily), then two cycles of bolus fluorouracil. The protocol was amended in March, 2005, to allow a neoadjuvant cohort in which patients in the capecitabine group received chemoradiotherapy (50·4 Gy plus capecitabine 1650 mg/m(2) daily) followed by radical surgery and five cycles of capecitabine (2500 mg/m(2) per day for 14 days) and patients in the fluorouracil group received chemoradiotherapy (50·4 Gy plus infusional fluorouracil 1000 mg/m(2) days 1-5 and 29-33) followed by radical surgery and four cycles of bolus fluorouracil (500 mg/m(2) for 5 days). Patients were randomly assigned to treatment group in a 1:1 ratio using permuted blocks, with stratification by centre and tumour stage. The primary endpoint was overall survival; analyses were done based on all patients with post-randomisation data. Non-inferiority of capecitabine in terms of 5-year overall survival was tested with a 12·5% margin. This trial is registered with ClinicalTrials.gov, number NCT01500993. FINDINGS: Between March, 2002, and December, 2007, 401 patients were randomly allocated; 392 patients were evaluable (197 in the capecitabine group, 195 in the fluorouracil group), with a median follow-up of 52 months (IQR 41-72). 5-year overall survival in the capecitabine group was non-inferior to that in the fluorouracil group (76% [95% CI 67-82] vs 67% [58-74]; p=0·0004; post-hoc test for superiority p=0·05). 3-year disease-free survival was 75% (95% CI 68-81) in the capecitabine group and 67% (59-73) in the fluorouracil group (p=0·07). Similar numbers of patients had local recurrences in each group (12 [6%] in the capecitabine group vs 14 [7%] in the fluorouracil group, p=0·67), but fewer patients developed distant metastases in the capecitabine group (37 [19%] vs 54 [28%]; p=0·04). Diarrhoea was the most common adverse event in both groups (any grade: 104 [53%] patients in the capecitabine group vs 85 [44%] in the fluorouracil group; grade 3-4: 17 [9%] vs four [2%]). Patients in the capecitabine group had more hand-foot skin reactions (62 [31%] any grade, four [2%] grade 3-4 vs three [2%] any grade, no grade 3-4), fatigue (55 [28%] any grade, no grade 3-4 vs 29 [15%], two [1%] grade 3-4), and proctitis (31 [16%] any grade, one [<1%] grade 3-4 vs ten [5%], one [<1%] grade 3-4) than did those in the fluorouracil group, whereas leucopenia was more frequent with fluorouracil than with capecitabine (68 [35%] any grade, 16 [8%] grade 3-4 vs 50 [25%] any grade, three [2%] grade 3-4). INTERPRETATION: Capecitabine could replace fluorouracil in adjuvant or neoadjuvant chemoradiotherapy regimens for patients with locally advanced rectal cancer. FUNDING: Roche Pharma AG (Grenzach-Wyhlen, Germany).

The effect of clinical pathways for bariatric surgery on perioperative quality of care.

BACKGROUND: Bariatric surgery demands a multidisciplinary approach and enhanced recovery schemes. Such schemes are complex and cumbersome to introduce into practice. This study evaluates if a clinical pathway (CP) facilitates implementation of an enhanced recovery scheme in bariatric surgery with the goal of improving perioperative quality of care. METHODS: We compared 65 consecutive patients who underwent bariatric surgery in 2009 and were treated with a CP (CP group) with 64 consecutive patients treated without CP in 2007/2008 (pre-CP group). Process quality indicators were catheter management, postoperative mobilization, spirometer training, vitamin B supplementation, diet resumption, intake of supplement drinks, and length of stay. Outcome quality was measured through morbidity, mortality, re-operations, and re-admissions. RESULTS: In the CP group, foley catheters were removed earlier (p < 0.0001), patients were mobilized more often on the surgery day (CP group 92.3% vs. pre-CP group 78.1%, p = 0.03), used spirometers more often (56.9% vs. 28.1%, p = 0.002), were more often supplemented with vitamin B (100% vs. 31.3%, p < 0.0001), and received oral supplement nutrition more often (100% vs. 59.4%, p < 0.0001). Median length of stay was shorter in the CP group (6 vs. 7 days, p = 0.007). There was no significant difference in mortality, morbidity, re-operations, and re-admissions. CONCLUSIONS: Following implementation of an enhanced recovery CP for bariatric surgery, several indicators of process quality improved while outcome quality remained unchanged. A CP seems useful for optimizing treatment of bariatric surgery patients according to enhanced recovery principles. However, future studies are required to better determine which elements of care can be improved most.

Expression of Transketolase like gene 1 (TKTL1) predicts disease-free survival in patients with locally advanced rectal cancer receiving neoadjuvant chemoradiotherapy.

BACKGROUND: For patients with locally advanced rectal cancer (LARC) neoadjuvant chemoradiotherapy is recommended as standard therapy. So far, no predictive or prognostic molecular factors for patients undergoing multimodal treatment are established. Increased angiogenesis and altered tumour metabolism as adaption to hypoxic conditions in cancers play an important role in tumour progression and metastasis. Enhanced expression of Vascular-endothelial-growth-factor-receptor (VEGF-R) and Transketolase-like-1 (TKTL1) are related to hypoxic conditions in tumours. In search for potential prognostic molecular markers we investigated the expression of VEGFR-1, VEGFR-2 and TKTL1 in patients with LARC treated with neoadjuvant chemoradiotherapy and cetuximab. METHODS: Tumour and corresponding normal tissue from pre-therapeutic biopsies of 33 patients (m: 23, f: 10; median age: 61 years) with LARC treated in phase-I and II trials with neoadjuvant chemoradiotherapy (cetuximab, irinotecan, capecitabine in combination with radiotherapy) were analysed by quantitative PCR. RESULTS: Significantly higher expression of VEGFR-1/2 was found in tumour tissue in pre-treatment biopsies as well as in resected specimen after neoadjuvant chemoradiotherapy compared to corresponding normal tissue. High TKTL1 expression significantly correlated with disease free survival. None of the markers had influence on early response parameters such as tumour regression grading. There was no correlation of gene expression between the investigated markers. CONCLUSION: High TKTL-1 expression correlates with poor prognosis in terms of 3 year disease-free survival in patients with LARC treated with intensified neoadjuvant chemoradiotherapy and may therefore serve as a molecular prognostic marker which should be further evaluated in randomised clinical trials.

KRAS and BRAF mutations and PTEN expression do not predict efficacy of cetuximab-based chemoradiotherapy in locally advanced rectal cancer.

PURPOSE: Mutations in KRAS and BRAF genes as well as the loss of expression of phosphatase and tensin homolog (PTEN) (deleted on chromosome 10) are associated with impaired activity of antibodies directed against epidermal growth factor receptor in patients with metastatic colorectal cancer. The predictive and prognostic value of the KRAS and BRAF point mutations as well as PTEN expression in patients with locally advanced rectal cancer (LARC) treated with cetuximab-based neoadjuvant chemoradiotherapy is unknown. METHODS AND MATERIALS: We have conducted phase I and II trials of the combination of weekly administration of cetuximab and irinotecan and daily doses of capecitabine in conjunction with radiotherapy (45 Gy plus 5.4 Gy) in patients with LARC (stage uT3/4 or uN+). The status of KRAS and BRAF mutations was determined with direct sequencing, and PTEN expression status was determined with immunohistochemistry testing of diagnostic tumor biopsies. Tumor regression was evaluated by using standardized regression grading, and disease-free survival (DFS) was calculated according to the Kaplan-Meier method. RESULTS: A total of 57 patients were available for analyses. A total of 31.6% of patients carried mutations in the KRAS genes. No BRAF mutations were found, while the loss of PTEN expression was observed in 9.6% of patients. Six patients achieved complete remission, and the 3-year DFS rate was 73%. No correlation was seen between tumor regression or DFS rate and a single marker or a combination of all markers. CONCLUSIONS: In the present series, no BRAF mutation was detected. The presence of KRAS mutations and loss of PTEN expression were not associated with impaired response to cetuximab-based chemoradiotherapy and 3-year DFS.

Hepaticojejunostomy--analysis of risk factors for postoperative bile leaks and surgical complications.

Anastomoses between the jejunum and the bile duct are an important component of many surgical procedures; however, risk factors for clinically relevant bile leaks have not yet been adequately defined. The objective of this study was to describe the incidence of bile leaks after hepaticojejunostomy and to define predictive factors associated with this risk and with surgical morbidity. Between October 2001 and April 2004, hepaticojejunostomies were performed in 519 patients in a standardized way. Patient- and treatment-related data were documented prospectively. A bile leak was defined as bilirubin concentration in the drains exceeding serum bilirubin with a consecutive change of clinical management or occurrence of a bilioma necessitating drainage. Surgical morbidity occurred in 15% of patients, the incidence of a bile leak was 5.6%. Multivariate analysis confirmed preoperative radiochemotherapy, preoperative low cholinesterase levels, biliary complications after liver transplantation necessitating a hepaticojejunostomy, and simultaneous liver resection as risk factors for bile leakages, whereas biliary complications after liver transplantation necessitating hepaticojejunostomy, simultaneous liver resection, and diabetes mellitus were significantly associated with postoperative surgical morbidity. Our results demonstrate that hepaticojejunostomy is a safe procedure if performed in a standardized fashion. The above found factors may help to better predict the risk for complications after hepaticojejunostomy.

Surgical technique for totally implantable access ports (TIAP) needs improvement: a multivariate analysis of 400 patients.

BACKGROUND: The objective of this study was to analyze factors that may have an impact on the failure rate of the surgical implantation technique for totally implantable access ports (TIAP) and to assess whether morbidity rates differ between a primarily successful surgical and a secondary Seldinger approach. METHODS: Four hundred consecutive patients receiving a primary TIAP in local anesthesia were included into this retrospective cohort study. A logistic regression-model was used to evaluate reasons for failure of the TIAP method. RESULTS: Three hundred eighteen (79.5%) patients had a successful TIAP procedure, 82 patients were intraoperatively converted to a Seldinger technique. Reasons for failure were: correct positioning impossible n = 54, no or only an undersized vessel for insertion available n = 17, other reasons n = 11. Logistic regression analysis did not reveal any significant factor for failure of the primary surgical approach. In the group with primarily successful TIAP, 8 of 318 patients (3%) developed complications compared to 7 of 82 patients (9%) converted to a Seldinger technique. CONCLUSION: Failure of the surgical approach for implanting totally implantable access ports is related to insertion and positioning. Conversion to a Seldinger technique results in a higher complication rate. A modified approach for surgical port placement should be considered in order to reduce complications.

Biofeedback versus electrostimulation in treatment of anal sphincter insufficiency.

The purpose of this study was to prospectively investigate a consecutive patient series (N = 70) with anal sphincter insufficiency and compare the efficacy of biofeedback and electrostimulation as conservative treatment options. Forty patients were treated by biofeedback training, 30 patients by electrostimulation. Patients were not specifically selected for one or the other treatment. Success was evaluated by vector volume manometry, water infusion test, time until stoma closure and clinical incontinence scores. Resting and squeeze pressure and resting and squeeze vector volume all increased significantly after biofeedback training (P < 0.05 and < 0.001). Resting pressure and squeeze vector volume only were significantly improved by electrostimulation (P < 0.05 and < 0.01). The increase in squeeze vector volume was significantly greater in the biofeedback group (P = 0.03). The estimated median time period from commencement of training until stoma closure was 9 months in the biofeedback versus 21 months in the electrostimulation group. Biofeedback training is probably superior to electrostimulation in the conservative treatment of anal sphincter insufficiency, this needs to be confirmed in a randomized study.