As with all pathology, prevention is better than cure. By focussing on the risk factors predisposing people to IBD-CRC it is hoped we can reduce the incidence of dysplasia and cancer. Any chemoprevention strategy must be acceptable to patients and physicians, in terms of safety, efficacy and cost. Ongoing colonic inflammation has been accepted as one of the causative factors behind IBD-CRC. Studies have focussed on using maintenance anti-inflammatory medications to prevent the development of dysplasia and cancer.
5-ASA compounds are used as maintenance therapy in colitis. In vitro studies found that they inhibit the nuclear factor kappa B pathway which is involved in tumour survival and sustaining chronic inflammation[4,56,57]. Due to the widespread use of 5-ASA compounds for maintenance therapy, prospective randomised trials are lacking with respect to chemoprevention. Velayos et al undertook a meta-analysis of 9 studies which included a total of 1932 patients with UC. They found a protective effect of 5-ASA against colorectal cancer (OR: 0.51; 95% CI: 0.37-0.69) and colorectal cancer/dysplasia as a combined end point (OR: 0.51; 95% CI: 0.38-0.69). They did not find an association between 5-ASA use and a lower risk of dysplasia (OR: 1.18; 95% CI: 0.41-3.43) although they make the point that only 2 of the studies looked at this endpoint.
Terdiman et al have reached a different conclusion with their observational study looking at the association between 5-ASA and IBD-CRC. They found that exposure to 5-ASA compounds during the 12 mo prior to the diagnosis of IBD-CRC was not associated with a decreased cancer risk (OR: 0.97; 95% CI: 0.77-1.23). They also found a non-statistically significant trend between a lower risk of IBD-CRC and an increased number of 5-ASA prescriptions in the previous year. Their conclusion was that 5-ASA compounds to do not have a protective effect against IBD-CRC when assessed over a short period. The important factor here seems to be the time period studied. Any preventative strategy has to be seen as a long term management approach. By using chemoprevention we are trying to prevent the genetic alterations which occur in the context of inflamed mucosa. The relationship between 5-ASA compounds and any protective effect must surely be assessed over a longer time period in order to discount it. The design of this study is too short and the results should be interpreted with caution.
The link between IBD-CRC and co-existent PSC is well established. The presence of additional bile acids in the colonic lumen is felt to contribute to this increased risk. Ursodeoxycholic acid (UDCA) decreases the amount of bile acids and studies have suggested treatment with UDCA may reduce the risk. Tung et al found a strong relationship between UDCA and a decreased risk of colonic dysplasia (OR: 0.18; 95% CI: 0.05-0.61). The relationship remained after adjusting for gender, age at diagnosis of colitis, duration of colitis, duration of PSC, severity of liver disease, and sulfasalazine use. Pardi et al also found a relative risk of 0.26 for colorectal dysplasia or cancer using UDCA when compared to placebo. These studies are in patients with colitis and PSC. The potential for using UDCA for patients with colitis only has not been explored. There are concerns about the side effects of using the medication in patients without PSC.
Given the potential benefit with suppression of inflammation, interest has been shown in other anti-inflammatory treatments. The role of steroids as chemopreventive agents has been explored. Evidence suggests a reduction in CRC risk with systemic and topical steroids[45,62]. However, the significant complications that occur with long-term steroid treatment make this strategy unacceptable. No chemopreventive effect has been shown with azathioprine or 6-mercaptopurine.
Other suggested therapies include folic acid and statins. Patients with IBD are at risk of folate deficiency. Studies have shown a protective trend against CRC but the effect is not statistically significant[64,65]. Potack et al suggest that given that folate is safe and inexpensive, supplementation should be considered for risk reduction. A study in Israel suggested statin therapy is associated with a risk reduction in sporadic CRC and a 94% risk reduction in patients with IBD. This potential benefit needs further investigation.
As described above, the quoted risk of developing cancer in colitis varies greatly from study to study. More recent population-based studies suggest a much lower risk than the earlier cohort studies. Methodological differences, the more recent widespread use of anti-inflammatory treatments and the advent of surveillance colonoscopy programmes may account for these differences. There is insufficient evidence to support the discontinuation of surveillance programmes and IBD is still believed to expose patients to an increased risk of CRC.
The aim of any screening or surveillance programme must be to identify early lesions to enable treatment and prevention before the development of invasive cancer. Prophylactic proctocolectomy eliminates the risk of CRC but this strategy is not acceptable to most patients or physicians. A surveillance programme must be acceptable to patients and practically possible to implement. The success of such programmes relies on patients engaging with follow up; they must understand the risks of not being tested and also that no surveillance strategy is without a miss rate.
Equally, physicians must implement the guidelines effectively. Many current guidelines advocate random quadrantic biopsies every 10 cm throughout the entire colon. This approach only visualises less than 1% of colonic mucosa. Rubin et al found the probability of detecting dysplasia was 90% if 33 and 95% if 56 biopsies were taken. Studies have shown that clinicians do not take sufficient biopsies[69,70].
The distinct differences between sporadic CRC and IBD-CRC are important for surveillance strategies. Bowel cancer screening in the general population relies on identification of adenomatous lesions which can be resected before they transform into carcinoma. IBD-CRC poses different challenges: dysplastic lesions do not follow the adenoma-carcinoma sequence, they can be difficult to see (flat lesions), difficult to resect completely, and multifocal. A meta-analysis of 1225 patients with UC found the likelihood of finding concurrent cancer at the time of colectomy for high or low grade dysplasia was 42% and 19%, respectively.
Due to the increased risk, patients diagnosed with PSC who are not previously known to have IBD should have a screening colonoscopy. For patients diagnosed with UC already, yearly surveillance colonoscopy should be performed from the point of diagnosis with PSC.
There has been increased focus on targeted biopsies and methods to improve identification of dysplastic lesions. Chromoendoscopy involves spraying dye (indigo carmine or methylene blue) on to the colonic mucosa to enable more detailed examination. Rutter et al compared consecutive, random and indigo carmine targeted biopsies. Chromoendoscopy found 7 dysplastic lesions in 157 targeted biopsies, compared to no dysplasia in 2904 non-targeted biopsies. Hurlstone et al conducted a prospective case-controlled study of 700 patients and also found a higher yield of dysplasia using indigo carmine chromoendoscopy as compared to conventional colonoscopy with random biopsies. They found 69 dysplastic lesions using chromoendoscopy and only 24 lesions with random biopsies (P < 0.001). These results are supported by Kiesslich et al, who found a statistically significantly higher rate of neoplasia detection with methylene blue chromoendoscopy.
Narrow band imaging (NBI) is available on most colonoscopes. It uses optical filter technology to improve the visibility of vessels, pit pattern and other soft tissue structures. Dekker et al performed a prospective, randomised trial to compare NBI and conventional colonoscopy. They did not find a statistically significant difference between the two methods; a similar number of dysplastic lesions were identified and missed using both methods.
Confocal laser endomicroscopy visualises the histology of the mucosa in real time. This is useful for characterising lesions rather than finding the lesion in the first place. Kiesslich et al compared confocal chromoscopic endomicroscopy with conventional colonoscopy with random biopsies in a randomised controlled trial. They found the yield of neoplasia was increased 4.75 times using the new approach (P = 0.005) using 50% less biopsies. Hurlstone et al compared confocal chromoscopic endomicroscopy to chromoendoscopy alone in a prospective, randomised controlled trial. They found that endomicroscopy increased the diagnostic yield of neoplasia 2.5 times.
However, it is already well known that there is significant inter-observer variability between even expert gastrointestinal pathologists when interpreting dysplasia. The use of confocal endomicroscopy requires the endoscopist to have the ability to interpret histological findings. For this modality to be widely used endoscopists would require extensive training to enable accuracy.
The best technique for surveillance is evolving. There is a move away from using random colonic biopsies towards targeted biopsies aimed at abnormal areas identified by newer colonoscopic techniques (chromoendoscopy, confocal microendoscopy). There has been concern regarding the specialist training needed for endoscopists to use chromoendoscopy effectively. Nevertheless, the 2010 guidelines from the British Society of Gastroenterology (BSG) recommend the use of chromoendoscopy with targeted biopsies for colitis surveillance.
Current guidance from the BSG advises all patients with IBD should have a screening colonoscopy approximately 10 years from symptom onset (ideally when in remission) with pancolonic dye spraying and targeted biopsies of abnormal areas. The risk of IBD-CRC is estimated based on duration and extent of disease, co-existent risk factors (PSC, family history of sporadic CRC), and the endoscopic and histological findings at colonoscopy. The surveillance intervals are based on this assessment of risk (Figure 1).
Figure 1 Surveillance recommendations for patients with colitis.
OR: Odds ratio; CRC: Colorectal cancer; PSC: Primary sclerosing cholangitis; FDR: First degree relative.
In conclusion, confirmed risk factors for IBD-CRC are duration, severity and extent of colitis, the presence of co-existent PSC and a family history of CRC. There is insufficient evidence currently to support an increased frequency of surveillance for patients diagnosed with IBD at a younger age. Evidence-based guidelines advise surveillance colonoscopy for patients with colitis 8 to 10 years after diagnosis, with the interval for further surveillance guided by risk factors (extent of disease, family history of CRC, post-inflammatory polyps, concomitant PSC, personal history of colonic dysplasia, colonic strictures)[78-80].