This paper is the second in a series of three publications relating to the European evidence-based consensus on the diagnosis and management of Crohn's disease and concerns the management of active disease, maintenance of medically induced remission and surgery. The aims and methods of the ECCO Consensus, as well as sections on diagnosis and classification are covered in the first paper [van Assche et al. JCC 2009a]. The final paper covers post-operative recurrence, fistulating disease, the management of paediatric and adolescent IBD, pregnancy, psychosomatics, extraintestinal manifestations and complementary or alternative therapy for Crohn's disease [Van Assche et al JCC 2009b]. #### Principal changes with respect to the 2006 ECCO guidelines

The early use of azathioprine/mercaptopurine or methotrexate in combination with steroids is an appropriate option in moderately active localised ileocaecal CD. Anti-TNF therapy should be considered as an alternative for patients with objective evidence of active disease who have previously been steroid-refractory, steroid-dependent, or steroid-intolerant (based on Statement 5B).

For those patients with severely active localised ileocaecal Crohn's disease and objective evidence of active disease who have relapsed, anti-TNF therapy with or without an immunomodulator is an appropriate option [EL1a, RG B for infliximab]. For some patients who have infrequently relapsing disease, restarting steroids with an immunomodulator may be appropriate (based on Statement 5C).

All currently available anti-TNF therapies appear to have generally similar efficacy and adverse-event profiles for inflammatory (‘luminal’) Crohn's disease, so the choice depends on availability, route of delivery, patient preference, cost and national guidelines \[EL5, RG D\] (Statement 5I).

Patients receiving azathioprine or mercaptopurine who relapse should be evaluated for adherence to therapy and have their dose optimised. Changing their maintenance therapy to methotrexate [EL1b RG B] or anti-TNF therapy [EL1a RGB] should be considered. Surgery should always be considered as an option in localised disease [EL4, …

/pdf/the-second-european-evidence-based-consensus-on-the-2blhqp1c4c.pdf

The second European evidence-based Consensus on the diagnosis and management of Crohn's disease: Current management

Results: Cancer-specific survival of all surgically treated patients was 68% at 5 years and 66% at 10 years. The local recurrence rate was 6% (95% confidence interval, 2%10%) at 5 years and 8% (95% confidence interval, 2%14%) at 10 years. In 405 “curative” resections, the local recurrence rate was 3% (95% confidence interval, 0%5%) at 5 years and 4% (95% confidence interval, 0%8%) at 10 years. Disease-free survival in this group was 80% at 5 years and 78% at 10 years. An analysis of histopathological risk factors for recurrence indicates only the Dukes stage, extramural vascular invasion, and tumor differentiation as variables in these results. Conclusions: Rectal cancer can be cured by surgical therapy alone in 2 of 3 patients undergoing surgical excision in all stages and in 4 of 5 patients having curative resections. In future clinical trials of adjuvant chemotherapy and radiotherapy, strategies should incorporate total mesorectal excision as the surgical procedure of choice.

The Basingstoke Experience of Total Mesorectal Excision, 1978-1997

Objective To examine the role of total mesorectal excision in the management of rectal cancer. Design A prospective consecutive case series. Setting A district hospital and referral center in Basingstoke, England. Patients Five hundred nineteen surgical patients with adenocarcinoma of the rectum treated for cure or palliation. Interventions Anterior resections (n=465) with low stapled anastomoses (407 total mesorectal excisions), abdominoperineal resections (n=37), Hartmann resections (n=10), local excisions (n=4), and laparotomy only (n=3). Preoperative radiotherapy was used in 49 patients (7 with abdominoperineal resections, 38 with anterior resections, 3 with Hartmann resections, and 1 with laparotomy). Main Outcome Measures Local recurrence and cancer-specific survival. Results Cancer-specific survival of all surgically treated patients was 68% at 5 years and 66% at 10 years. The local recurrence rate was 6% (95% confidence interval, 2%-10%) at 5 years and 8% (95% confidence interval, 2%-14%) at 10 years. In 405 "curative" resections, the local recurrence rate was 3% (95% confidence interval, 0%-5%) at 5 years and 4% (95% confidence interval, 0%-8%) at 10 years. Disease-free survival in this group was 80% at 5 years and 78% at 10 years. An analysis of histopathological risk factors for recurrence indicates only the Dukes stage, extramural vascular invasion, and tumor differentiation as variables in these results. Conclusions Rectal cancer can be cured by surgical therapy alone in 2 of 3 patients undergoing surgical excision in all stages and in 4 of 5 patients having curative resections. In future clinical trials of adjuvant chemotherapy and radiotherapy, strategies should incorporate total mesorectal excision as the surgical procedure of choice.

https://jamanetwork.com/journals/jamasurgery/articlepdf/211692/SPC8025.pdf

Rectal Cancer: The Basingstoke Experience of Total Mesorectal Excision, 1978-1997

http://pic2.cmt.com.cn/WebImages/Res/20121218/20121218_07b349d6-2637-4801-bdbd-4fb2c4b2a867.pdf

Management of Crohn's Disease in Adults

Definition and grading of anastomotic leakage following anterior resection of the rectum: a proposal by the International Study Group of Rectal Cancer.

OBJECTIVE: The aim of this randomized multicenter trial was to assess the rate of symptomatic anastomotic leakage in patients operated on with low anterior resection for rectal cancer and who were ...

Defunctioning stoma reduces symptomatic anastomotic leakage after low anterior resection of the rectum for cancer : A randomized multicenter trial

Objective. Surgical technique and peri-operative management of rectal carcinoma have developed substantially in the last decades. Despite this, morbidity and mortality after anterior resection of the rectum are still important problems. The aim of this study was to identify risk factors for anastomotic leakage in anterior resection and to assess the role of a temporary stoma and the need for urgent re-operations in relation to anastomotic leakage.Patients and methods. In a nine-year period, from 1987 to 1995, a total of 6833 patients underwent elective anterior resection of the rectum in Sweden. A random sample of 432 of these patients was analysed (sample size 6.3%). The associations between death and 10 patient-and surgery-related variables were studied by univariate and multivariate analysis. Data were obtained by review of the hospital files from all patients.Results. The incidence of symptomatic clinically evident anastomotic leakage was 12% (53/432). The 30-day mortality was 2.1% (140/6833). The rate of mortality associated with leakage was 7.5%. A temporary stoma was initially fashioned in 17% (72/432) of the patients, and 15% (11/72) with a temporary stoma had a clinical leakage, compared with 12% (42/360) without a temporary stoma, not significant. Multivariate analysis showed that low anastomosis (≤ 6 cm), pre-operative radiation, presence of intra-opcrative adverse events and male gender were independent risk factors for leakage. The risk for permanent stoma after leakage was 25%. Females with stoma leaked in 3% compared to men with stoma who leaked in 29%. The median hospital stay for patients Arithout leakage was 10 days (range 5-61 days) and for patients with leakage 22 days (3-110 days).Conclusion. In this population based study, 12% of the patients had symptomatic anastomotic leakage after anterior resection of the rectum. Postoperative 30-day mortality was 2.1%. Low anastomosis, pre-operative radiation, presence of intra-operative adverse events and male gender were independent risk factors for symptomatic anastomotic leakage in the multivariate analysis. There was no difference in the use of temporary stoma in patients with or without anastomotic leakage.

Risk factors for anastomotic leakage after anterior resection of the rectum

ObjectiveThe authors compared clinical bowel function and complications of a low anterior resection with either a straight or colonic J pouch anastomosis.Summary Background DataUrgency and frequent bowel movements after rectal resection with a low anastomosis have been related to the loss of rectal

Randomized comparison of straight and colonic J pouch anastomosis after low anterior resection.

Summary Background Radiotherapy reduces the risk of local recurrence in rectal cancer. However, the optimal radiotherapy fractionation and interval between radiotherapy and surgery is still under debate. We aimed to study recurrence in patients randomised between three different radiotherapy regimens with respect to fractionation and time to surgery. Methods In this multicentre, randomised, non-blinded, phase 3, non-inferiority trial (Stockholm III), all patients with a biopsy-proven adenocarcinoma of the rectum, without signs of non-resectability or distant metastases, without severe cardiovascular comorbidity, and planned for an abdominal resection from 18 Swedish hospitals were eligible. Participants were randomly assigned with permuted blocks, stratified by participating centre, to receive either 5 × 5 Gy radiation dose with surgery within 1 week (short-course radiotherapy) or after 4–8 weeks (short-course radiotherapy with delay) or 25 × 2 Gy radiation dose with surgery after 4–8 weeks (long-course radiotherapy with delay). After a protocol amendment, randomisation could include all three treatments or just the two short-course radiotherapy treatments, per hospital preference. The primary endpoint was time to local recurrence calculated from the date of randomisation to the date of local recurrence. Comparisons between treatment groups were deemed non-inferior if the upper limit of a double-sided 90% CI for the hazard ratio (HR) did not exceed 1·7. Patients were analysed according to intention to treat for all endpoints. This study is registered with ClinicalTrials.gov, number NCT00904813. Findings Between Oct 5, 1998, and Jan 31, 2013, 840 patients were recruited and randomised; 385 patients in the three-arm randomisation, of whom 129 patients were randomly assigned to short-course radiotherapy, 128 to short-course radiotherapy with delay, and 128 to long-course radiotherapy with delay, and 455 patients in the two-arm randomisation, of whom 228 were randomly assigned to short-course radiotherapy and 227 to short-course radiotherapy with delay. In patients with any local recurrence, median time from date of randomisation to local recurrence in the pooled short-course radiotherapy comparison was 33·4 months (range 18·2–62·2) in the short-course radiotherapy group and 19·3 months (8·5–39·5) in the short-course radiotherapy with delay group. Median time to local recurrence in the long-course radiotherapy with delay group was 33·3 months (range 17·8–114·3). Cumulative incidence of local recurrence in the whole trial was eight of 357 patients who received short-course radiotherapy, ten of 355 who received short-course radiotherapy with delay, and seven of 128 who received long-course radiotherapy (HR vs short-course radiotherapy: short-course radiotherapy with delay 1·44 [95% CI 0·41–5·11]; long-course radiotherapy with delay 2·24 [0·71–7·10]; p=0·48; both deemed non-inferior). Acute radiation-induced toxicity was recorded in one patient ( vs short-course radiotherapy: short-course radiotherapy with delay 0·59 [95% CI 0·36–0·97], long-course radiotherapy with delay 0·63 [0·38–1·04], p=0·075). However, in a pooled analysis of the two short-course radiotherapy regimens, the risk of postoperative complications was significantly lower after short-course radiotherapy with delay than after short-course radiotherapy (144 [53%] of 355 vs 188 [41%] of 357; OR 0·61 [95% CI 0·45–0·83] p=0·001). Interpretation Delaying surgery after short-course radiotherapy gives similar oncological results compared with short-course radiotherapy with immediate surgery. Long-course radiotherapy with delay is similar to both short-course radiotherapy regimens, but prolongs the treatment time substantially. Although radiation-induced toxicity was seen after short-course radiotherapy with delay, postoperative complications were significantly reduced compared with short-course radiotherapy. Based on these findings, we suggest that short-course radiotherapy with delay to surgery is a useful alternative to conventional short-course radiotherapy with immediate surgery. Funding Swedish Research Council, Swedish Cancer Society, Stockholm Cancer Society, and the Regional Agreement on Medical Training and Clinical Research in Stockholm.

Optimal fractionation of preoperative radiotherapy and timing to surgery for rectal cancer (Stockholm III): a multicentre, randomised, non-blinded, phase 3, non-inferiority trial

Early results after rectal cancer surgery in a defined population were compared before and after the introduction of total mesorectal excision. In the first period (1984–1986) 211 cases of rectal cancer were diagnosed and in the second (1990–1992) 230. Of these, 134 patients in the first period (group 1) had anterior resection or abdominoperineal excision which was considered curative. In the second period 128 curative anterior resections and abdominoperineal excisions were performed by a limited number of surgeons familiar with total mesorectal excision (group 2). No differences between the groups were found in stage distribution, rate of curative operations, postoperative complications or postoperative mortality. Local recurrence had developed in 19 patients in group 1 and in eight in group 2, 1 year after the end of the study periods (P = 0·03). Local radicality was in doubt in 13 patients in group 1 and in eight in group 2. In the remaining 121 and 120 patients, 13 and four local recurrences respectively were present (P = 0·03). Actuarial analysis showed a significant reduction in local recurrence rate (P = 0·03) and an increase in crude survival (P = 0·03) at 4 years in group 2 compared with group 1. Total mesorectal excision reduces the local recurrence rate after excision of rectal cancer.

Olof Hallböök

Papers

Defunctioning stoma reduces symptomatic anastomotic leakage after low anterior resection of the rectum for cancer : A randomized multicenter trial

Risk factors for anastomotic leakage after anterior resection of the rectum

Randomized comparison of straight and colonic J pouch anastomosis after low anterior resection.

Optimal fractionation of preoperative radiotherapy and timing to surgery for rectal cancer (Stockholm III): a multicentre, randomised, non-blinded, phase 3, non-inferiority trial

Local recurrence following total mesorectal excision for rectal cancer.