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Chemoprevention of Colitis-Associated Dysplasia or Cancer in Inflammatory Bowel Disease

The association between inflammatory bowel disease and colorectal cancer is well known. Although the overall incidence of inflammatory bowel disease has declined recently, patients with this disease still have a 1.7-fold increased risk of colorectal cancer. The risk factors for developing colorectal cancer include extensive colitis, young age at diagnosis, disease duration, primary sclerosing cholangitis, chronic colonic mucosal inflammation, dysplasia lesion, and post-inflammatory polyps. In patients with inflammatory bowel disease, control of chronic inflammation and surveillance colonoscopies are important for the prevention of colorectal cancer. The 2017 guidelines from the European Crohn’s and Colitis Organisation suggest that colonoscopies to screen for colorectal cancer should be performed when inflammatory bowel disease symptoms have lasted for 8 years. Current evidence supports the use of chemoprevention therapy with mesalamine to reduce the risk of colorectal cancer in patients with ulcerative colitis. Other compounds, including thiopurine, folic acid, statin, and tumor necrosis factor-α inhibitor, are controversial. Large surveillance cohort studies with longer follow-up duration are needed to evaluate the impact of drugs on colorectal cancer risks.


INTRODUCTION
Inflammatory bowel disease (IBD), especially ulcerative colitis (UC), is associated with an increased risk of colorectal cancer (CRC). [1][2][3][4][5] A 2001 meta-analysis reported that the prevalence of CRC was approximately 3.7% in patients of UC patients and the cumulative risk after 10 and 30 years was 2% and 18%, respectively. 6 A recent populationbased study demonstrated a lower incidence of CRC in UC patients of 0.06% to 0.15% and a lower cumulative risk of 2.1% to 7.5% after 30 years of UC. [7][8][9][10][11][12][13][14] In IBD, chronic inflammation with oxidative stress may interact with genes involved in carcinogenic pathways. 15 Unlike sporadic CRC, the "inflammation-dysplasiacarcinoma" pathway causes a series of genetic alterations in IBD-related CRC. 16 Toll-like receptors and tumor necrosis factor-α (TNF-α) activate nuclear factor-κB (NF-κB), an inflammatory factor. NF-κB induces transcription of genes involved in tumorigenesis, such as cyclooxygenase-2 (COX-2), inducible nitric oxide synthase, and angiogenic factors. 17 In the early phase of dysplasia, inflammation may induce apoptosis via tumor suppressor p53 pathways. Compared with sporadic CRC, the onset of p53 mutations is earlier in IBD-related CRC. 18 The final key gene in IBDrelated CRC, just prior to carcinoma, is nonfunctional adenomatous polyposis coli. Unstable chromosomes or veillance strategies, and chemoprevention of colitis-related CRC and dysplasia in IBD patients are discussed.

Risk factors of CRC for patients diagnosed IBD
The 2017 European Crohn's and Colitis Organisation (ECCO) consensus reported several risk factors for CRC in IBD patients. 21 The risk factors included disease duration 6,8,22,23 and extensive colitis. 23 Compared to the general population, the risk of CRC was 1.7-fold higher for proctitis, 2.8-fold higher for left side colitis, and 14.8-fold higher for pancolitis. 24 The histological extent was associated with highgrade dysplasia and CRC. 25,26 Non-polypoid (hazard ratio [HR], 8.6; 95% confidence interval [CI], 3.0 to 24.8) or dysplastic lesions more than 1 cm in size (HR, 3.8; 95% CI, 1.5 to 13.4) and a dysplasia lesion history (HR, 2.8; 95% CI, 1.2 to 6.5) were risk factors for developing high-grade dysplasia or CRC in another study. 26 The most consistent risk factor for CRC is primary sclerosing cholangitis (PSC), which increases the absolute risk of CRC by up to 31%. [27][28][29] Family history of CRC also increases the risk of CRC in patients with UC. 30 Inflammatory complications, such as post-inflammatory polyps, foreshortened colon, and strictures, are associated with CRC. 31 35 The 2017 ECCO guideline suggests that a colonoscopy to screen CRC should be performed after 8 years of IBD symptoms. 21 The next surveillance colonoscopy should be arranged in 1 year for patients with high-risk features, such as severe active inflammation, dysplasia, colon stricture, or PSC. The next surveillance should be scheduled at 2 to 3 years for patients with intermediate risk factors, including post-inflammatory polyps, mild-to-moderate active inflammation of extensive colitis, or patient's first-degree relative with CRC at age of 50 years and above. The next surveillance colonoscopy should be scheduled after 5 years in patients without high or intermediate risks. 21 A 2019 meta-analysis to evaluate different colonoscopy methods for the detection of dysplasia in IBD patients included ten studies, and six studies were randomized controlled trials (RCTs). Three RCTs favored chromoendoscopy for the detection of dysplasia more than light endoscopy (relative risk [RR], 1.50; 95% CI, 1.08 to 2.10), and the results for chromoendoscopy were similar to highdefinition white-light endoscopy (HDWLE) (RR, 1.36; 95% CI, 0.84 to 2.18). 36 In non-RCTs, chromoendoscopy was superior to both HDWLE and standard-definition white-light endoscopy (SDWLE) for the detection of dysplasia lesion in IBD patients (RR, 3.48; 95% CI, 2.11 to 5.73; SDWLE: RR, 6.85; 95% CI, 2.79 to 16.81; HDWLE: RR, 2.57; 95% CI, 1.41 to 4.68). 36 One RCT included targeted and random biopsies (quadrantic biopsies every 10 cm) for surveillance colonoscopy; the neoplasm detection rate was similar (target biopsy group, 11.4%; random biopsy group, 9.3%; p=0.617). 37 Chromoendoscopy with targeted biopsies was recommended in the 2017 ECCO consensus for the detection of dysplasia in IBD patients. Alternatively, when white-light colonoscopy is used, targeted and random biopsies should be collected for any visible lesions. 21 Endoscopic artificial intelligence with deep learning or machine learning is being developed in recently years. [38][39][40][41][42][43] Application of such technology is promising to assess mucosal healing and predict disease relapse for IBD patients. 39,44 The use of such technology may improve the ability of endoscopist to detect dysplasia for IBD patients. 45

Chemoprevention with 5-aminosalicylic acid
In 1994, Pinczowski et al. 46 first reported the chemopreventive effects of sulfasalazine in IBD patients. Threemonth treatment with sulfasalazine significantly protected UC patients from CRC. Interest in chemopreventive therapies for IBD patients was provoked by these findings. The structural analog of aspirin, 5-aminosalicylic acid (5-ASA), has chemopreventive activity via different pathways. 47 Induction of S phase arrest by 5-ASA improves DNA fidelity and, consequently, reduces mutation rates. 48,49 Nitric oxide synthase activity and the generation of reactive oxygen species are also reduced, protecting patients from free radical damage. 50,51 Suppression of the epidermal growth factor pathway and downregulation of c-Myc lead to apoptosis. 52,53 The Wnt/beta-catenin pathway is modulated and the tumor suppressor peroxisome proliferator-activated receptor-γ (PPAR-γ) is upregulated by 5-ASA, leading to inhibition of cell proliferation. 54 Finally, 5-ASA inhibits the NF-κB pathway and blocks both COX-2-dependent and COX-2-independent cancer cell growth. 55,56 In a case-control study nested in the CESAME cohort study, propensity scores were adjusted for 5-ASA treatment. The sub-analysis in patients diagnosed with IBD showed a protective effect for patients with long-standing extensive colitis (OR, 0.5; 95% CI, 0.2 to 0.9). 57 A population-based cohort study in Hong Kong included 2,103 IBD patients (857 Crohn's disease and 1,246 UC); this study showed no cancer risk reduction after adjustment for age, gender, and smoking status (adjust HR, 1.22; 95% CI, 0.6 to 2.5). 58 Meta-analysis can provide recommendations from heterogeneous data. In a meta-analysis of 17 studies, 5-ASA was associated with a lower risk of developing CRC/dysplasia in UC patients in both population-and clinical-based studies (OR, 0.46; 95% CI, 0.34 to 0.61). The pooled analysis revealed no protective effects against CRC/ dysplasia in Crohn's disease patients in either the clinical-or population-based studies (OR, 0.66; 95% CI, 0.42 to 1.03). This meta-analysis also analyzed the impact of different types and dosages of 5-ASA (mesalazine and sulfasalazine) on CRC/dysplasia development. Mesalazine at ≥1.2 g/day was more protective than lower dosages. However, sulfasalazine use showed no protective effects against CRC/dysplasia at either ≥2.0 g/day or <2.0 g/day. The most protective effects of 5-ASA were detected in patients from Asian countries (OR, 0.25; 95% CI, 0.14 to 0.47). The second most protective effect was found in European patients (OR, 0.55; 95% CI, 0.42 to 0.73). However, no significant protective effects of 5-ASA against CRC were detected in North American IBD patients (OR, 0.67; 95% CI, 0.44 to 1.02). 59 Two other meta-analyses showed similar results. 60,61 In a recent meta-analysis, a multivariable analysis of six studies showed a lower risk of CRC in patients treated with 5-ASA (pool OR, 0.51; 95% CI, 0.39 to 0.66). The 2017 ECCO consensus states that mesalamine compounds may decrease the incidence of CRC in UC. 21

Chemoprevention with thiopurines
The anti-inflammatory thiopurines were used to maintain IBD patients during remission to avoid prolonged steroid use. 62,63 In a French long-term follow-up study of 19,486 patients, a decreased risk of CRC/high-grade dysplasia was observed in patients with long-term extensive colitis after treatment with thiopurines compared to patients who were never treated with thiopurines (HR, 0.28; 95% CI, 0.09 to 0.89). 64 However, in the same patient group, thiopurines were associated with an increased risk of lymphoproliferative malignancy (HR, 52.5). When comparing patients receiving thiopurines versus patients who had never received the drugs, the multivariate-adjusted analysis for lymphoproliferative disorder showed a hazard ratio of 5.28 (95% CI, 2.01 to 13.9; p=0.0007). 65 Another meta-analysis of 76,999 patients to assess the correlation between thiopurine treatment and CRC risk in IBD patients showed significant protective effects in UC patients (OR, 0.67; 95% CI, 0.45 to 0.98). However, there was no significant protective effect in UC patients (OR, 1.06; 95% CI, 0.54 to 2.09). 66 Another meta-analysis of 11 cohort studies and 16 case-control studies, which included 95,397 IBD patients, showed a risk reduction in high-grade dysplasia and CRC both in case-control and cohort studies. In patients with high CRC risk, the chemopreventive effects were significant in patients with disease duration over 8 years with an OR of 0.47 in case-control studies (95% CI, 0.31 to 0.70) and a RR of 0.96 in cohort studies (95% CI, 0.94 to 0.98). However, protective effects in IBD patients with PSC or extensive colitis were not demonstrated in this study. 67 Despite the decreased risk of CRC in IBD patients, thiopurines may have carcinogenic effects. As a result, the 2017 ECCO consensus did not recommend for or against chemoprevention with thiopurines. 21

Chemoprevention with statins
Statins are hydroxymethylglutaryl coenzyme A reductase inhibitors that decrease cholesterol synthesis and increase the removal of low-density lipoprotein. These drugs are widely used in patients with hyperlipidemia. Statins may also have a role in CRC prevention and treatment. 68 Several studies demonstrated the chemopreventive effects of statins on CRC via effects on inflammation-induced colon cancer proliferation, potential effects on vascular endothelial growth factor inhibitors, and effects on intracellular oxidative stress and apoptosis. [69][70][71][72] Nevertheless, studies assessing the effects of statins on CRC in IBD patients are scarce.
One study showed a risk reduction in IBD-related CRC (OR, 0.07; 95% CI, 0.01 to 0.78) and non-IBD-related CRC (OR, 0.49; 95% CI, 0.39 to 0.62) after long-term statin use. 73 According to a multivariate analysis, statin treatment reduced the risk of CRC development in IBD patients (OR, 0.42; 95% CI, 0.28 to 0.62). 74 However, a cohort study from Mount Sinai Hospital showed no difference in CRC risk despite statin use (adjust HR, 0.98; 95% CI, 0.43 to 2.25). 75 Therefore, the chemopreventive effects of statins in IBD patients remain controversial.

Chemoprevention with ursodeoxycholic acid
Patients with both IBD and PSC have a 5-to 9-fold higher risk of CRC than the risk in patients with IBD alone. [76][77][78][79] High levels of bile acids in the colon may have carcinogen effects, resulting in the proliferation of colonic epithelial cells, which eventually leads to dysplasia or CRC. 80,81 Therefore, investigators hypothesized that ursodeoxycholic acid may decrease colonic dysplasia in patients with UC and PSC (OR, 0.18; 95% CI, 0.05 to 0.61). 82 In a recent meta-analysis including eight studies (five observational, three RCTs), ursodeoxycholic acid did not significantly protect against CRC (OR, 0.81; 95% CI, 0.41 to 1.61). 80 Nevertheless, a significant protective effect against developing CRC and/or high-grade dysplasia was detected (OR, 0.35; 95% CI, 0.17 to 0.73). 80

Chemoprevention with biologics
Biologics, such as anti-TNF-α, were first employed as induction therapy for severe colitis that was refractory to intravenous corticosteroid. 62 Cancer preventive effects of infliximab, an anti-TNF-α, were demonstrated in animal models. The early administration of infliximab induces significant anti-mutagenic actions, apoptosis of inflammatory cells, attenuation of TNF-α levels, and suppression of β-catenin accumulation, which all contribute to the attenuation of colonic tumor formation. 83 A Quebec claims database study from Canada 84 including 19,582 patients found anti-TNF exposure was not associated with an increased risk of CRC in IBD patients. In a Dutch case-control study from 78 general hospitals, chemopreventive effects on CRC were detected in response to anti-TNF-α treatment in IBD patients (OR, 0.09; 95% CI, 0.01 to 0.68; p=0.02). 85 A large cohort study enrolled 225,090 individuals with Crohn's disease and 188,420 with UC between 1999 and 2020 from the multicenter database (Explorys) in the United States was the first to show the inverse association of anti-TNF therapy and CRC. 86 Anti-TNF-α treatment reduced the risk of developing CRC in Crohn's disease (OR, 0.69; 95% CI, 0.66 to 0.73; p<0.0001) and UC patients (OR, 0.78; 95% CI, 0.73 to 0.83; p<0.0001). 86 Further prospective studies are warranted to evaluate anti-TNF-α drugs as chemoprotective agents in patients with IBD. Current available guidelines do not recommend for or against chemopreven-tion with anti-TNF-α or other newer biologic agents. 62,87

Chemoprevention with folic acid
Several solid tumors, including lung, breast, pancreas, and cervical, and CRCs, are associated with decreased folate levels. 88,89 Folate deficiency may occur in IBD patients due to poor nutrition, competitive inhibition of intestinal absorption by sulfasalazine, and excessive intestinal losses. 90,91 In one meta-analysis of 10 studies with 4,517 patients, folate supplementation had a protective effect against CRC development (pool HR, 0.58; 95% CI, 0.37 to 0.80). 92 Chemoprevention with folate is feasible due to low costs and good tolerability and safety. Further prospective studies are needed to define the chemopreventive influence of folate supplements.

Chemoprevention with nonsteroidal antiinflammatory drug
Nonsteroidal anti-inflammatory drugs (NSAIDs) are thought to decrease the risk of IBD-related CRC by blocking the COX-2 pathway. 17 A case-controlled study from 2006 reported decreased CRC risk in IBD patients using a multiple variable model (OR, 0.10; 95% CI, 0.03 to 0.33). 93 However, recent studies did not confirm these protective effects. 85,94 One meta-analysis in 2016 included eight studies with 14,917 patients. No significant effects of NSAIDs on CRC risk were detected. The pooled adjusted OR of CRC development after exposure to NSAIDs was 0.80 (95% CI, 0.39 to 1.21). 95 Despite the high heterogeneity in these studies, chemoprevention with NSAID did not exhibit protective effects.

Chemoprevention with acetylsalicylic acid
The potential effects of acetylsalicylic acid (aspirin) on IBD-related CRC have been investigated. In three studies including 1,282 patients, no protective effect of aspirin against CRC development in IBD patients was detected (adjusted OR, 0.66; 95% CI, 0.06 to 1.39). 95 However, these studies did not record the accurate dose and duration of aspirin treatment. Favorable effects of aspirin were reported with longer duration of use (the risk reduction was 20% after 5 years of use and 30% after 10 years of use) and increasing dosage (100 mg/day conveys a risk reduction of 10%, and 325 mg/day conveys a risk reduction of 35%). 96 Currently, the evidence does not support the protective effect of aspirin against IBD-CRC. Table 1 summarizes the different consensus guidelines. The British Society of Gastroenterology (BSG), 97 ECCO, 62 and the Japanese Society of Gastroenterology recom-mended 5-ASA. 98 The recommendation was strong, but the evidence was moderate to low-quality. Thiopurine was suggested by the BSG. 97 However, the recommendation was weak and the evidence was low. The American College of Gastroenterology suggested good control of chronic inflammation and a surveillance strategy to prevent CRC development. 99 Despite several cohort studies and metaanalyses showing chemopreventive effects of 5-ASA and thiopurine against CRC, the data were inconsistent when adjusting for confounding factors, including inflammation severity.

CONCLUSIONS
The overall prevalence of IBD-related CRC declined recently, but IBD patients still have a 1.7-fold increased risk of CRC. Controlled chronic inflammation and surveillance colonoscopy are important for the prevention of CRC in IBD patients. According to the 2017 ECCO consensus, the first colonoscopy should be scheduled 8 years after the onset of symptoms, and the next surveillance should be scheduled in 1 to 5 years according to the risk factors. Current evidence supports chemoprevention with mesalamine to reduce CRC among UC patients. Other compounds, including thiopurine, folic acid, statins, and TNF-α inhibitors, are controversial. An RCT to investigate the effects of chemoprevention is not feasible and would be unethical. However, large surveillance cohort studies with longer follow-up times are required to evaluate the impact of drugs on CRC risks.

CONFLICTS OF INTEREST
No potential conflict of interest relevant to this article was reported.