Essential updates 2018/2019: Colorectal (benign)

Abstract This review outlines current topics on the surgical treatment of benign colorectal diseases, with a focus on inflammatory bowel disease (IBD) and diverticulitis. Treatment options for IBD and diverticulitis have evolved in the last few years as a result of medical advances in technology and new clinical trials. Therefore, treatment options and strategies need to be updated to provide optimal care for patients. The purpose of this review is to elucidate recent global trends and update the surgical treatment strategy for IBD and diverticulitis based on literature published in the past 2 years. Prevalence of IBD, including ulcerative colitis and Crohn's disease, has increased over the last few decades. During this period, many new medical therapies were introduced for the treatment of IBD, including biological therapy, immunomodulators, and leukocyte apheresis therapy. As a result, new surgical strategies for IBD are required. In order to improve surgical outcomes in IBD patients, the influence of preoperative treatment on postoperative complications needs to be considered. The incidence of diverticulitis is also increasing with lifestyle changes and increasing numbers of older people. For diverticulitis with perforation and generalized peritonitis, surgery is the gold standard. Elective surgery after conservative treatment of diverticulitis is also an option because of high recurrence rates. With an increase in diverticulitis, systematic strategies are essential for an appropriate approach to diverticulitis, taking into account various factors, including the patient's background.

remitting conditions and chronic inflammation in the intestine. 3,4 Development and/or pathogenesis of IBD is considered to be an inadequate immune response to luminal contents. New medical therapies have been rapidly introduced for the treatment of IBD, such as biological therapy, immunomodulators, and leukocyte apheresis therapy, among others. 5,6 Surgical treatments corresponding to these changes are also needed. In contrast, a diverticulum is a small outpouching from the intestinal lumen due mostly to mucosal herniation through the wall at sites of vascular perforation. 2,7 Diverticulitis is inflammation or infection of the diverticulum, which occurs mostly in the colon. In Japan, diverticulosis is increasing because of a widespread elderly population and changing lifestyle. Approximately 80% of patients with diverticulosis remain asymptomatic, and the other 20% of patients develop diverticulitis, requiring medical treatment. 2 It is expected that the needs for surgical treatment of IBD and

| INFL AMMATORY BOWEL D IS E A S E
Inflammatory bowel disease is a chronic disease that causes unexplained inflammation in the gastrointestinal tract and comprises UC and CD. The number of patients is increasing globally, as well as in Japan. 8,9 Abnormalities in the gut immune system are thought to be highly involved in the development of IBD, but the exact pathogenic mechanism is unclear. 2,8 As both UC and CD often occur in young people and require long-term treatment, they not only lower the quality of life (QOL), but hinder social activities, such as schooling, work, marriage, and childbirth. In addition, new problems, such as inflammation-related carcinogenesis, have emerged with an increase in long-term cases. 10 Biological therapy based on disease mechanisms appeared in the 2000s. Patients' QOL improved, and both medical treatment and surgical treatment changed significantly. A study of US patients between 2009 and 2015 showed that the use of biological therapy increased from 20% to 40% in CD patients, and from 5% to 16% in UC patients. 11 Kimura et al 12 showed that in 2011, Japanese patients treated with a biological preoperatively increased dramatically, and that in 2013, 41% of UC patients who underwent surgery had received biological treatment. Japanese nationwide cohort study also showed the rate of administration of anti-tumor necrosis factor (TNF) increased from 0.3% in 2007 to 43% in 2017 among UC patients who underwent restorative proctocolectomy. 13 Given the continuous emergence of biological therapies used more frequently in severe IBD, we are in a new era of biological therapy, including anti-TNFα, anti-interleukin (IL)-12/23p40, anti-integrin α4β7, and Janus kinase inhibitor, which will likely continue for some time. Assessment of variability in real-world practice is essential to optimize the timing of initial therapy and surgery for IBD patients. According to a study of regional differences in the treatment of IBD after 2006, 66% of CD and 28% of UC patients in the USA commonly used biological therapy, compared to 19% of CD and 0% of UC patients in China.
No differences were seen in the proportion of patients undergoing early surgery. 14 With regard to surgical treatment, preoperative conditions in IBD are often immunosuppressive or patients are undernourished, and different from other bowel diseases, such as colorectal cancer.
This section outlines points to be aware of in the surgical treatment of UC and CD.

| Surgical treatment and biological therapy
Several reports, including randomized controlled trials, assessed preoperative treatment and surgical rates. The Active Ulcerative Colitis Trial (ACT) reported the efficacy of infliximab for induction and maintenance therapy and the cumulative incidence of colectomy in 728 patients with moderate-to-severe active UC. Patients receiving infliximab had a decreased Mayo score with decreased rectal bleeding compared to placebo patients. At 54 weeks of follow up, the colectomy rate was 10% in the infliximab group and 17% in the placebo group; which means the absolute risk of colectomy decreased by 7%. 15,16 Another study evaluated the short-and longterm efficacy of infliximab in 45 patients with steroid-resistant UC (24 infliximab and 21 placebo); 29% in the infliximab group and 67% in the placebo group underwent colectomy within 3 months, and 50% in the infliximab group and 76% in the placebo group within 3 years. No patient death was reported. Patients who had endoscopic remission within 3 months did not require colectomy, even after 3 years. The main benefit of infliximab occurred within the first 3 months, and early mucosal healing reduced the risk of subsequent colectomy. 17,18 The CONSTRUCT study showed the efficacy of infliximab and cyclosporine in 270 patients with steroid-resistant UC. The colectomy rate within 3 years was 41% in the infliximab group and 48% in the cyclosporine group, and no significant differences were observed between the two groups. 19 Laharie et al also reported the colectomy rates within 3 months for 115 patients with steroid-resistant UC: 21% in the infliximab group and 17% in cyclosporine group. The 5-year colectomy-free survival rate was not different between the infliximab group and the cyclosporine group (65% vs 62%, respectively). Death directly related to UC or treatment was not observed. 20,21 A meta-analysis showed short-term clinical response rates in 72.1%, clinical remission rates in 52.4%, and 3-month colectomy rates in 10.1% among patients receiving tacrolimus with moderate-to-severe and steroid-refractory UC. No significant difference was seen for tacrolimus compared with anti-TNF with regard to clinical remission rate, clinical response rate, and 3-month colectomy rate. 22 Narula et al reported the efficacy of anti-TNF agents and calcineurin inhibitors including tacrolimus and cyclosporine for 314 patients with severe steroid-refractory UC.
Patients with sequential treatment achieved short-term response in 62.4% and remission in 38.9%; however, the colectomy rates were high with 28.3% at 3 months and 42.3% at 12 months. 23 Takeuchi et al 24 also showed that tacrolimus and infliximab were equally effective in short-term clinical remission and response rates, and in colectomy-free rates for active UC.

| Surgical treatment
When emergency subtotal colectomy is carried out, we usually select i.p. placement of the closed rectal stump in order to prevent inflammatory adhesion at the next remnant rectal resection.
Bedrikovetski et al carried out a systematic review of the appropriate management of rectal stumps after emergency subtotal colectomy in patients with acute severe UC. A total of 476 patients were assessed regarding closed s.c. placement of the rectal stump, i.p. placement, or mucous fistula formation. Pelvic sepsis rates were lowest (2%) in patients with s.c. placement. Patients with i.p. placement had less wound infection but high mortality. 27 Risk factors in patients with chronic refractory UC were an absence of clinical response and lack of mucosal healing after induction with biological therapy. Early assessment (12-16 weeks after therapy) of the clinical and endoscopic response could predict subsequent risk of colectomy. 28 In CD, perianal lesions relapse the same as intestinal lesions, and exacerbation of lesions or inappropriate surgical treatment leads to decreased anal function and QOL. Selection of appropriate treatment is necessary for surgeons to maintain anal function. With progress in medical treatment for IBD, surgical indications and prognosis have changed. The treatment effect should be evaluated early, and surgical treatment should be carried out before the general condition worsens without continuing with inadequate medical treatment for a long period of time.

| Postoperative complications
Crohn's disease cannot be completely cured by surgery, and redo surgery for recurrence is often necessary. For efficient prevention of postoperative recurrence, it is essential to identify high-risk cases of recurrence. The relationship between preoperative biological therapy and postoperative complications has been studied, but is still con- Another case-matched analysis showed that exposure to preoperative vedolizumab was not associated with increased morbidity, but the majority of patients had an ostomy. 35 The impact of biologicals on postoperative complications is still controversial. Summary of previous reports is shown in Table 1. 23,30,[32][33][34][35][36][37][38][39][40][41][42] Large prospective studies are required to draw conclusions.
Inflammatory bowel disease is associated with a 1.5-to 3-fold increased risk of venous thromboembolism (VTE). Sarlos et al reported the risk of VTE during corticosteroid or anti-TNFα therapy in 58 518 patients with IBD. VTE events occurred in 5.6% of patients. The corticosteroid group had a significantly higher incidence of VTE. In contrast, anti-TNFα therapy had a fivefold lower risk of VTE compared to corticosteroids. 43

| Positioning of surgical treatment
The LIR!C trial evaluated the cost-effectiveness of laparoscopic ileocecal resection compared to infliximab in CD patients who failed more than 3 months of conventional immunomodulator or steroid therapy without signs of critical strictures. A total of 143 patients were included in this randomized trial, and total direct healthcare and social costs were lower in the resection group than in the infliximab group. Laparoscopic ileocecal resection is a cost-effective treatment compared to infliximab. 46 Murthy et al evaluated the impact of infliximab on hospitalization, surgery rates, and costs in IBD patients living in Ontario, Canada. The introduction of infliximab did not result in a significant reduction in hospitalization and surgery rates among CD patients, whereas the hospitalization rates declined substantially among UC patients. They reported a threefold increase in drug costs for CD patients following the introduction of infliximab, but no significant change in UC patients. 47 The CONSTRUCT study showed the use of cyclosporine led to lower total costs compared to infliximab in UC patients.
Nevertheless, no significant difference was found between these drugs regarding clinical effectiveness, colectomy rates, incidence of side-effects, or mortality 1-3 years post-treatment. However, participants were more positive about infliximab than cyclosporine, and nurses disliked the i.v. cyclosporine. 19 In recent years, enhanced recovery after surgery (ERAS) has been shown to reduce length of hospital stay, complications, and costs after colorectal surgery, but the effect on IBD has been unclear. Liska et al reported an improvement in outcomes using ERAS in 671 IBD patients. Implementation of ERAS for IBD patients resulted in a decrease in length of hospital stay and costs without any increase in complications and readmissions. 48 Robotic surgery for IBD has gradually spread, but the hybrid approach would currently be optimal for complicated cases. 49 Mizushima et al 50 reported that single-incision laparoscopic surgery can be carried out safely in patients with stricturing or penetrating CD. In UC patients undergoing ileal pouch-anal anastomosis, the 30-day postoperative complication rate was comparable to laparoscopic surgery. 51 The use of open, laparoscopic, and robotic surgery should be balanced with cost-effectiveness and postoperative outcomes.

| Bariatric surgery for IBD patients
In recent years, the relationship between obesity and IBD has attracted attention. Cañete

| Surgical procedure
Hartmann's operation has been carried out conventionally for complicated diverticulitis. The Hartmann operation has the challenge of stoma reversal and 30%-40% of stoma cannot be closed. 63,64 Primary resection and anastomosis, and laparoscopic lavage are widespread as an alternative surgery. The LADIES trial assessed outcomes after Hartmann's procedure versus sigmoidectomy and primary anastomosis with or without protective ileostomy in 133 patients with severe sigmoid diverticulitis (Hinchey III or IV disease) aged <85 years. Twelve-month stoma-free survival was significantly better in patients with primary anastomosis, and no significant differences were observed in short-term morbidity and mortality between the two procedures. 65 Several studies have reported that primary anastomosis was similar to Hartmann's operation regarding major postoperative complications, mortality, and readmission rate. 66 The authors reported no difference in readmissions or mortality between these procedures. 72

| Postoperative complications and longterm outcomes
The DIRECT trial showed significantly better QOL (less pain, lower risk of new recurrences) at the 5-year follow up in patients who underwent elective sigmoidectomy compared to conservative treatment for recurring diverticulitis and/or ongoing complaints after an episode of diverticulitis. Forty-six percent of patients with conservative treatment required surgery as a result of severe ongoing complaints. 79 This trial also showed that elective sigmoidectomy is cost-effective compared to conservative treatment. 80 Risk factors and postoperative outcomes were evaluated in patients who underwent surgery for diverticulitis. Emergency surgery was associated with worse preoperative conditions and more postoperative complications, including mortality. Patients with comorbid conditions may be a better population for elective colectomy. 81 An et al 54  short-term treatment failure, emergency surgery, or long-term surgery. Abscesses more than 3 cm were associated with shortterm treatment failure, and abscesses more than 5 cm were associated with the need for surgery. 83 After surgery for diverticulitis, patients with metabolic syndrome (BMI >30 kg/m 2 , hypertension, and DM) had more adverse events, such as reintubation, ventilator dependence more than 48 hours, myocardial infarction, and superficial or deep surgical site infections. Patients with metabolic syndrome also had longer recovery and higher rates of complications, readmissions, and mortality. 84 Bordeianou

| CON CLUS IONS
In the present review, we updated advancements in the surgical treatment of IBD and diverticulitis based on recent findings. The prevalence of these diseases will increase in the future as already seen in developed countries. Although surgical technology, including robotic surgery, is rapidly progressing, surgeons need to carry out the most appropriate treatment to prevent unfavorable outcomes for patients. Not only colorectal surgeons, but also general surgeons, should always keep in touch with these novel ideas and concepts to improve the QOL of patients.

D I SCLOS U R E
Conflicts of Interest: Authors declare no conflicts of interest for this article.