2015-04-16 14:54:54 UTC

Managing CRC Risk in IBD Patients

Colorectal Neoplasia in Inflammatory Bowel Disease, Diagnosis and Management

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The AGA Institute Medical Position Panel consisted of the authors of the technical review, a community-based gastroenterologist (Robert P. McCabe, MD, Minnesota Gastroenterology), academic-based gastroenterologists (Themistocles Dassopoulos, MD, James D. Lewis, MD, and Thomas A. Ullman, MD), an insurance provider representative (Tom James III, MD Physician Advisor, Strategic Advisory Group, Humana), a colon and rectal surgeon (Robin McLeod, MD, Mount Sinai Hospital-Canada), a pathologist (Lawrence J. Burgart, MD, Minnesota Gastroenterology), chair of the AGA Institute Clinical Practice and Quality Management Committee (John Allen, MD, Minnesota Gastroenterology), and chair of the Practice Management and Economics Committee (Joel V. Brill, MD, Predictive Health, LLC).

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In this medical position statement, a series of questions were identified that are relevant for clinicians who manage patients with inflammatory bowel disease (IBD) at risk for colorectal neoplasia (Table 1). For each question, a comprehensive literature search was conducted, pertinent evidence was reviewed, and the quality of relevant data was evaluated. The details of the methodology used for the literature search associated with answering each of the questions appear in the following text. The conclusions were based on the best available evidence or, in the absence of quality evidence, the expert opinion of the authors of the technical review1 and the medical position statement. Some of the conclusions constitute recommendations for prevention. The strength of these recommendations was weighed using the US Preventive Services Task Force (USPSTF) grades, which are detailed in Table 2.

Table 1Questions Relevant for Clinicians Who Manage Patients With IBD at Risk for Colorectal Neoplasia
  • 1

    Are patients with IBD at increased risk for colorectal cancer?

  • 2

    Are there well-substantiated factors other than dysplasia that increase or decrease the risk of CRC in IBD?

  • 3

    What is the natural history of dysplasia?

  • 4

    Should colectomy be performed for raised dysplasia?

  • 5

    Should colectomy be performed for flat dysplasia?

  • 6

    Is there sufficient rationale for performing surveillance colonoscopy in patients with IBD?

  • 7

    How should surveillance colonoscopy be performed?

  • 8

    What role do the newer imaging techniques play in identifying and managing dysplasia?

  • 9

    Should chemopreventive agents be used to lower the risk of developing dysplasia or CRC in IBD?

  • 10

    Should molecular markers be applied to help stratify patients into low- and high-risk groups?

Table 2USPSTF Recommendations and Grades
Strength of recommendations:
Grade A indicates that the certainty of evidence is high that the magnitude of net benefits is substantial. The USPSTF recommends providing the service for the specific population.
Grade B indicates that the certainty of evidence is moderate that the magnitude of net benefits is either moderate or substantial, or that the certainty of evidence is high that the magnitude of net benefits is moderate. The USPSTF recommends providing the service for the specific population.
Grade C indicates that the certainty of the evidence is either high or moderate that the magnitude of net benefits is small. The USPTF recommends against routinely providing the service for the specific population. There may be considerations that support providing the service in an individual patient.
Grade D indicates that the certainty of the evidence is high or moderate that the magnitude of net benefits is either zero or negative. The USPSTF recommends against providing the service for the specific population.
Grade I indicates that the evidence is insufficient to determine the relationship between benefits and harms (ie, net benefit). The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of the service in the specific population.
US Preventive Services Task Force Procedure Manual. AHRQ Publication No. 08-05118-EF, July 2008. Available at: http://www.ahrq.gov/clinic/uspstf08/methods/procmanual.htm.

Literature Search Methodology

A search of the MEDLINE database was performed to identify relevant English language articles published in peer-reviewed journals. For this search, the terms dysplasia, colorectal cancer, surveillance, polyp, chemoprevention, chromoendoscopy, endoscopy, primary sclerosing cholangitis, risk factors, and children were searched in combination with the terms ulcerative colitis, Crohn's disease, Crohn's colitis, colitis, or inflammatory bowel disease. A manual search of the reference lists from the potentially relevant papers was performed to identify additional studies that may have been missed using the computer-assisted strategy. In most instances, the pathology studies represented retrospective case-control, or cohort studies, descriptive studies, reports of expert committees, or opinions of respected authorities in pathology practice.

Are Patients With IBD at Increased Risk for Colorectal Cancer?

  • Patients with ulcerative colitis and Crohn's disease of the colon have an increased risk of developing colorectal cancer.
     

Patients with IBD have an increased risk of developing colorectal cancer (CRC). The exact magnitude of the risk is uncertain due to wide variations in risk reported in many studies. Variations occur because some studies reported data only from tertiary referral centers, some were population based, and others represented only case reports or small series. Meta-analyses have been performed in both patients with ulcerative colitis (UC) and patients with Crohn's disease (CD).

From one large meta-analysis, the risk of cancer in patients with UC is estimated at 2% after 10 years, 8% after 20 years, and 18% after 30 years of disease. Data from a UK 30-year surveillance program calculated the risk of cancer and dysplasia to be 7.7% at 20 years and 15.8% at 30 years. Subsequent population-based studies have suggested that the risk may not be this high and that the risk has actually decreased over time. This may be due to widespread use of aminosalicylates, which are believed to have a chemoprotective effect, or to more liberal and early use of colectomy for medically refractory disease in some centers, and possibly surveillance colonoscopy.

In CD, there has also been wide variation in the reported risk of CRC due to inconsistencies in studies. For instance, some studies only included patients with small bowel disease and colonic resections, and others did not account for duration of disease. Two meta-analyses that adjusted for these factors have reported the standardized incidence ratio for CRC as 2.5 (95% confidence interval [CI], 1.7—3.5) and the relative risk (RR) as 4.5 (95% CI, 1.3—14.9). Studies that included patients with both UC and CD have shown the risk to be roughly equivalent in both diseases (RR of 2.75 and 2.64, respectively). In addition, many of the characteristics of CRC in UC and CD have been shown to be similar. Thus, extensive Crohn's colitis should raise the same concerns regarding CRC risk as UC.

Are There Well-Substantiated Factors Other Than Dysplasia That Increase or Decrease the Risk of CRC in IBD?

  • Disease duration, more extensive disease, primary sclerosing cholangitis, and a positive family history of sporadic CRC are all associated with an increased risk of CRC.
  • Colonic strictures in patients with UC and/or a shortened colon, and/or multiple postinflammatory pseudopolyps increase the risk of CRC.
  • Inflammation is a risk factor for progression to colorectal neoplasia.

 

Increasing duration of disease is firmly established as one of the most important risk factors for the development of CRC in patients with IBD. The risk of CRC is significant after 8 years of disease and increases in subsequent years. A small proportion of cancers may arise before 8 years, but because this is so infrequent, it does not justify commencing surveillance earlier than 8 years. Rather, it is more appropriate to focus surveillance on patients who have a higher risk as a result of other risk factors.

Extent of disease is also a major risk factor for CRC in patients with IBD. Most cancers arise in patients with pancolitis. There is an intermediate risk for patients with left-sided disease (disease up to the splenic flexure), whereas patients with proctitis or ulcerative proctosigmoiditis have either little or no increased risk of CRC. Extent of disease is defined by the most extensive disease identified at any time histologically. A colonoscopy is advised after 8 years of disease to redefine the extent of disease and to decide on subsequent surveillance intervals. Two studies have examined backwash ileitis as an independent risk factor for development of CRC. These studies showed contrasting results. Thus, at present, there is insufficient evidence to consider backwash ileitis as an independent risk factor for CRC in patients with IBD.

There is good evidence showing that primary sclerosing cholangitis (PSC) is associated with an increased risk of CRC. From one meta-analysis, the risk of CRC was calculated to be increased 4-fold compared to patients with UC but without PSC. The increased risk was shown to persist after liver transplantation, at a rate of 1% per person per year. Patients with PSC may have subclinical UC for many years before their diagnosis of PSC. Thus, patients with UC (or Crohn's colitis) and PSC are recommended to commence annual colonoscopy from the time of diagnosis of PSC and are also recommended to continue surveillance after (possible) liver transplantation.

A positive family history of sporadic CRC in a first-degree relative of a patient with IBD doubles the risk of CRC. The risk increases 9-fold if the first-degree relative was younger than 50 years of age at the time of diagnosis of CRC. A positive family history should be regarded as an important independent risk factor, but it is not yet clear whether this variable should influence surveillance intervals.

A greater degree of macroscopic and histologic inflammation is associated with an increased risk of cancer. CRC can arise in areas of endoscopically normal but histologically active colitis. CRC can also occur in areas where active colitis has remitted, that is, areas where there is no active inflammation but where there may be histologic findings of inactive colitis, such as crypt distortion. Lack of endoscopic inflammation at the time of detection of neoplasia does not mean that there was an absence of inflammation in the area of neoplasia before its development. The risk of neoplasia is not increased in mucosa that has never been inflamed. Thus, histologic rather than macroscopic changes of disease are a better determinant of the presence or absence of inflammation for the purpose of assessing cancer risk. For the purpose of surveillance, extent of disease should be defined histologically. For example, a patient with evidence of endoscopic disease up to 10 cm but with active or chronic inflammation (or documented evidence of previous inflammation) up to 60 cm documented histologically, should be surveyed as if he or she has left-sided colitis and not proctitis.

It has been reported that strictures, especially in UC, and the presence of a shortened colon (representing long-standing inflammation) are associated with an increased risk of CRC. Extra vigilance is required by the colonoscopist in patients with any of these features, and extra biopsies are highly recommended. Multiple postinflammatory pseudopolyps have been shown to double the risk of CRC. Surveillance may have reduced benefit in the context of multiple pseudopolyps, and thus affected patients should be made aware of this limitation. Some patients may choose prophylactic colectomy over continued surveillance in this circumstance.

Early age at onset of IBD symptoms has not been consistently shown to represent an independent risk factor of CRC. It has been reported that the cumulative risk of CRC in patients with extensive UC is 40% in whom the disease began before 15 years of age and 25% in patients who develop UC between 15 and 39 years of age. Other data that suggest an increased risk of CRC in patients with IBD diagnosed after the age of 40 years may reflect a contribution from the age-related risk of developing sporadic CRC. Children diagnosed with IBD have at least an equivalent rate of CRC development compared to patients diagnosed at an older age. Thus, surveillance should be conducted as frequently in children as in adults and should be based on duration of disease, not chronological age.

What Is the Natural History of Dysplasia?

  • In most cases, CRC in IBD develops from dysplasia.
  • Although imperfect, dysplasia is currently considered the best marker of CRC risk in IBD.
     

Dysplasia is currently considered the best marker of CRC risk in IBD, but there are limitations in predicting the natural history of dysplasia. Although dysplasia is present in 75% to 90% of patients with cancer, CRC can develop in patients without a prior history of dysplasia. Also, not all patients with low-grade dysplasia (LGD) will progress through a phase of detectable high-grade dysplasia (HGD) before developing cancer. Importantly, the interpretation of dysplasia in mucosal biopsy specimens is subject to a high level of interobserver variability. Thus, pathologists with particular expertise in gastrointestinal disorders should review all cases diagnosed as indefinite, LGD, or HGD. Until more reliable markers of cancer risk are identified, clinical management depends on the endoscopic and histologic identification of dysplasia in mucosal biopsy specimens of the colon. In patients found to have dysplasia on one colonoscopy, the absence of dysplasia on follow-up colonoscopy does not provide reassurance that the risk of CRC has declined. Patients with biopsy specimens that show indefinite dysplasia have a risk of progression to HGD or CRC higher than in patients without dysplasia. Unifocal low-grade dysplasia has been shown to carry a similar risk of CRC as multifocal dysplasia in one study, but this remains to be confirmed in other studies.

Should Colectomy Be Performed for Raised Dysplasia?

Grade A: High certainty that the magnitude of net benefits is substantial.

  • Patients with IBD and a non–adenoma-like dysplasia-associated lesion or mass should be treated with colectomy.
  • Patients with IBD and an adenoma-like dysplasia-associated lesion or mass, and no evidence of flat dysplasia elsewhere in the colon, can be managed safely by polypectomy and continued surveillance.
     

Raised, endoscopically visible, dysplastic lesions in IBD have been referred to by the acronym "DALM" (dysplasia-associated lesion or mass). Recent studies suggest that IBD-related DALMs may be broadly separated into those that appear similar to sporadic adenomas in non-IBD patients, referred to as adenoma-like DALMs, and those that do not resemble adenoma-like DALMs, which are referred to as non—adenoma-like DALMs. Both types of DALMs are typically composed of dysplastic columnar cells that resemble those of sporadic neoplasia. Adenoma-like DALMs represent well-circumscribed, smooth or papillary nonnecrotic, sessile or pedunculated polyps that are usually readily accessible to removal by routine endoscopic methods. Other synonyms used to describe this lesion include adenoma-like polyp, adenoma-like dysplastic polyp, polypoid dysplasia, and adenoma-like mass. Non—adenoma-like DALMs include velvety patches, plaques, irregular bumps and nodules, wart-like thickenings, stricturing lesions, and broad-based masses. In the literature, until recently both adenoma-like and non—adenoma-like DALMs were often referred to simply by the term "DALM" without regard to their endoscopic appearance. Non—adenoma-like and adenoma-like DALMs are best differentiated on the basis of their endoscopic features because there is much overlap in the histologic, immunohistochemical, and molecular features between these 2 types of lesions.

Non—adenoma-like DALMs represent a heterogeneous group of dysplastic lesions that have been shown to have a strong positive association with synchronous and metachronous carcinoma. In fact, in many instances, biopsy specimens of these lesions simply represent the surface of an underlying carcinoma. The association of cancer with non—adenoma-like DALMs ranges from 38% to 83% in several retrospective cohort studies.

In contrast, adenoma-like DALMs represent well-circumscribed dysplastic lesions that appear endoscopically and pathologically similar to sporadic adenomas. There have been several retrospective case-control studies designed specifically to evaluate features that may help differentiate IBD-related adenoma-like DALMs from sporadic adenomas by histologic, immunohistochemical, or molecular methods. Although some features, such as young age at diagnosis, longer duration of disease, prominent villous architecture, a mixture of normal and dysplastic epithelium at the surface of the polyp, "bottom-up" as opposed to "top-down" dysplasia, increased inflammation in the polyp, presence of stalk dysplasia, and a high frequency of p53 and a low frequency of KRAS mutations, have been shown to be associated with IBD-related adenoma-like DALMs, none have proven to be specific enough to be used in individual patients. If the surrounding flat mucosa adjacent to the dysplastic polyp also shows flat dysplasia, the adenoma-like DALM is more likely considered IBD related. This is based on the presumption that dysplasia in UC arises as a generalized field effect.

Adenoma-like DALMs that occur outside, or proximal to, areas of mucosa involved with inflammatory disease are considered sporadic in origin and can be managed conservatively with polypectomy under the strong presumption that neoplasia in IBD arises only in areas of chronically inflamed mucosa. Patients with IBD and an adenoma-like DALM within an area of inflammatory disease may be treated adequately by polypectomy and continued surveillance if there is no evidence of flat dysplasia in adjacent mucosa, regardless of the underlying pathogenesis (whether IBD related or sporadic). Several prospective studies have confirmed an extremely low rate of dysplasia and/or cancer in patients with IBD and an adenoma-like DALM, ranging from 0 to 4.6%. The outcome of patients with UC or CD and an adenoma-like DALM is similar regardless of the degree of dysplasia in the polyp. Therefore, based on these retrospective and prospective studies, there is good evidence to support the concept that nonsurgical treatment of adenoma-like DALMs in IBD by polypectomy and continued surveillance is a safe approach if there is no evidence of flat dysplasia elsewhere in the colon.

Should Colectomy Be Performed for Flat Dysplasia?

Grade A: There is high certainty that colectomy for flat HGD treats undiagnosed synchronous cancer and prevents metachronous cancer.

Grade Insufficient: The current evidence is insufficient to assess the balance of benefits and harms of colectomy for flat LGD.

"Flat dysplasia" is a term that has been applied to lesions that are not raised, minimally raised, or sometimes invisible. Not all studies have clearly defined what is meant by "flat dysplasia," making comparisons between studies somewhat difficult. With this caveat in mind, if flat dysplasia is identified within colitic mucosa, unless it can be successfully and completely removed endoscopically, strong consideration should be given to colectomy as the treatment of choice. Regarding patients with flat HGD, synchronous CRC may be present in 42% to 67% of cases. If immediate colectomy is not performed in patients with HGD when first detected, CRC develops in 25% to 32% of patients on long-term follow-up. Therefore, although the evidence is considered to be of fair quality due to its retrospective nature, there is general consensus among experts in the field that colectomy is recommended for patients with flat HGD.

The management of patients with LGD is more controversial. There is an approximate 19% to 27% prevalence rate of synchronous CRC in patients who have undergone colectomy within a few months of colonoscopy that only showed LGD as the most advanced histologic abnormality. One recent meta-analysis revealed that the positive predictive value for progression to HGD and/or CRC from LGD is about 18%. However, significant variability in progression to HGD or CRC has been noted between various studies. Some reveal a progression rate of LGD to advanced neoplasia (HGD or cancer) that ranges from as low as 0 to 3% over 10 years to 35% to 54% over 5 years.

Thus, the decision to undergo colectomy versus continued surveillance in the setting of flat LGD should be individualized and discussed at length among the patient, the gastroenterologist, and the colorectal surgeon. For instance, if flat LGD is detected in biopsy specimens on more than one occasion, is multifocal (detected at more than one site in the colon), or is found at the time of initial screening colonoscopy (prevalent dysplasia), stronger consideration should be given to recommending colectomy. Once again, a pathologist with particular expertise in gastrointestinal pathology should review all biopsy specimens diagnosed initially as indefinite, LGD, or HGD.

Is There Sufficient Rationale for Performing Surveillance Colonoscopy in Patients With IBD?

Grade B: There is moderate certainty that surveillance colonoscopy results in at least moderate reduction of CRC risk in patients with IBD.

  • Despite the lack of randomized controlled trials, surveillance colonoscopy is recommended for patients with IBD at increased risk for developing CRC.
  • Patients with extensive UC or CD of the colon are most likely to benefit from surveillance.
     

Proof that surveillance colonoscopy is effective in patients with IBD requires demonstration of a reduction in mortality due to CRC. Randomized controlled trials testing surveillance colonoscopy have not been performed. In addition, randomized trials are not likely to be performed because of ethical issues related to withholding surveillance from a control group and the long duration of follow-up needed to demonstrate a survival advantage. Nevertheless, a large number of case series and 3 case-control studies have suggested clinical benefit of surveillance colonoscopy for patients with IBD. However, the Cochrane Group performed a pooled analysis of published studies in patients with UC and concluded that there is no clear evidence that surveillance colonoscopy prolongs survival in patients with extensive colitis. There was evidence that cancers tended to be detected at an earlier stage in patients who had undergone surveillance, and had a better prognosis, compared to patients who had not undergone surveillance. One important limitation of the studies was the potential for lead-time bias to contribute to the apparent benefit of surveillance colonoscopy. Thus, there is indirect evidence that surveillance is effective at reducing the risk of death from IBD-associated CRC.

In balance, patients should be advised that surveillance colonoscopy offers a reasonable chance of detecting dysplasia or early-stage CRC. Patients with ulcerative proctitis, ulcerative proctosigmoiditis, or limited Crohn's colitis do not require surveillance colonoscopy but should follow age-specific guidelines for CRC screening.

How Should Surveillance Colonoscopy Be Performed?

  • The technique of surveillance colonoscopy in patients with IBD should include extensive biopsies of all anatomic segments of colorectal mucosa.
  • Although there are inadequate data available to recommend optimal surveillance intervals, intervals of 1 to 3 years are suggested.
  • Careful inspection of the mucosa along with a sufficient number of biopsy specimens should be obtained from all anatomic segments of the colon.

 

To date, our understanding of the efficacy of surveillance colonoscopy is based on studies that used random biopsies of colorectal mucosa, with targeted biopsies only if suspicious lesions were noted at endoscopy. Recommendations regarding the preferred method of performing surveillance colonoscopy are also based largely on the opinion of international IBD experts. Surveillance colonoscopy is performed in a rather inconsistent manner by physicians worldwide. One study suggested that to detect dysplasia and/or cancer, rigorous surveillance colonoscopy must be performed, including the acquisition of at least 33 random biopsy specimens from all portions of the colon in patients with pancolitis. Because dysplasia and cancer are more common in the left colon, it is also recommended that more extensive sampling should be performed in the left colon and particularly the rectum. Biopsy specimens should also be obtained separately from areas of flat mucosa surrounding the base of adenoma-like and non—adenoma-like DALMs. Equally important to obtaining a sufficient number of biopsy specimens is careful visual inspection of the colorectal mucosa during colonoscopy.

Chromoendoscopy, or other image-enhancing techniques, are recommended for physicians with experience with these techniques. With the use of enhanced endoscopic techniques, targeted biopsies may be performed as an alternative to obtaining random biopsy specimens (see the next section). Poor adherence of patients to their surveillance program reduces the effectiveness of surveillance. The currently recommended guidelines regarding surveillance colonoscopy are summarized as follows:

  • 1

    All patients, regardless of the extent of disease at initial diagnosis, should undergo a screening colonoscopy a maximum of 8 years after onset of symptoms, with multiple biopsy specimens obtained throughout the entire colon to assess the true microscopic extent of inflammation.

  • 2

    Patients with ulcerative proctitis or ulcerative proctosigmoiditis are not considered at increased risk for IBD-related CRC and thus may be managed on the basis of average-risk recommendations.

  • 3

    Patients with extensive or left-sided colitis should begin surveillance within 1 to 2 years after the initial screening endoscopy.

  • 4

    The optimal surveillance interval has not been clearly defined. After 2 negative examinations (no dysplasia or cancer), further surveillance examinations should be performed every 1 to 3 years. Recent data suggests that increasing the frequency of surveillance colonoscopy to every 1 to 2 years after 20 years of disease is not needed for all patients but should be individualized according to the presence or absence of other risk factors (see the next section).

  • 5

    There are no prospective studies that have determined the optimal number of biopsy specimens that should be obtained to detect dysplasia reliably. Representative biopsy specimens from each anatomic section of the colon should be obtained. One study has recommended that a minimum of 33 biopsy specimens be taken in patients with pancolitis.

  • 6

    Because the sensitivity for detecting dysplasia by chromoendoscopy is higher than that of white light endoscopy, chromoendoscopy with targeted biopsies is recommended as an alternative to random biopsies for endoscopists who have expertise with this technique (see the next section).

  • 7

    Patients with PSC should begin surveillance colonoscopy at the time of this diagnosis and then undergo yearly colonoscopy thereafter.

  • 8

    Ideally, surveillance colonoscopy should be performed when the colonic disease is in remission.

  • 9

    Patients with a history of CRC in first-degree relatives, ongoing active endoscopic or histologic inflammation, or anatomic abnormalities such as a foreshortened colon, stricture, or multiple inflammatory pseudopolyps may benefit from more frequent surveillance examinations.

  • 10

    These recommendations also apply to patients with Crohn's colitis who have disease involving at least one third of the length of the colon.

 

What Role Do the Newer Imaging Techniques Play in Identifying and Managing Dysplasia?

  • The sensitivity of chromoendoscopy for detecting dysplasia is higher than white light endoscopy in the hands of endoscopists who have expertise with this technique.
  • The natural history of chromoendoscopically detected dysplasia is unknown.
  • Additional studies are needed to evaluate the efficiency of other imaging methods, such as narrow band imaging and confocal endomicroscopy, in detecting dysplasia.

Several imaging modalities, such as chromoendoscopy with methylene blue or indigo carmine, narrow band imaging, and confocal endomicroscopy, are currently being studied as potential alternatives to white light endoscopy. Several randomized studies suggest that chromoendoscopy increases the yield of detecting dysplasia and may obviate the need for multiple random biopsies. However, despite improved detection methods of dysplastic lesions, in instances where colectomy has been performed based on chromoendoscopy findings, unexpected cancers have not yet been reported. The performance of chromoendoscopy is subject to the skill of the endoscopist. In addition, high-definition technology and enhanced magnification, is rendering white light colonoscopy more accurate in detecting dysplasia. Thus, at this time, normal white light colonoscopy, using standard or high-definition colonoscopes along with multiple colon biopsies, remains a reasonable method of surveillance for patients with IBD. However, chromoendoscopy with targeted biopsies is considered an acceptable alternative to white light endoscopy for endoscopists who have experience with this technique. Training issues and the time required for surveillance examinations need to be addressed carefully before chromoendoscopy is to be considered the new standard method of endoscopic surveillance. Consideration should be given to referring selected high-risk patients to experts who specialize in the performance of enhanced endoscopic imaging techniques for surveillance.

Should Chemopreventive Agents Be Used to Lower the Risk of Developing Dysplasia or CRC in IBD?

 

Grade A: High certainty that the magnitude of net benefits is substantial.

  • I

    Ursodeoxycholic acid has demonstrated a significant reduction in CRC in patients with UC who also have PSC.

Grade B: Moderate certainty that the magnitude of net benefits is moderate.

  • Aminosalicylates are chemopreventive against CRC.

Grade D: High certainty that the magnitude of net benefits is negative.

  • Oral or topical corticosteroids, while demonstrating antineoplastic effects in 2 studies, are associated with too many side effects to warrant use as chemopreventive agents.

Grade Insufficient: No recommendation, insufficient evidence to recommend for or against the use of thiopurines, supplements, or statins.

  • Azathioprine or 6-mercaptopurine has not been consistently associated with lower rates of CRC.
  • Folic acid supplements, calcium, multivitamins, or statins have not been consistently associated with lower rates of CRC.

 

Chemopreventive agents that have been studied in IBD include aminosalicylates (mesalamine), corticosteroids, immunomodulators, folic acid, and ursodeoxycholic acid (UDCA). Unfortunately, there are no prospective, randomized, controlled trials that have evaluated the utility of chemopreventive agents in decreasing the risk of CRC in patients with IBD. Given the large number of patients needed to perform these types of studies, they are not likely to be performed in the near future. With the exception of 2 prospective studies of UDCA in patients with UC who also have PSC, all other studies of chemopreventive agents have been retrospective in design, with a few studies drawing their conclusions from population-based registries or pharmaceutical databases. Studies also vary as to whether the end point of the study is CRC, versus HGD or CRC. Furthermore, in some recent studies, the type of chemopreventive agent was not the primary variable under study.

UDCA is commonly used in patients with UC who also have PSC. Indeed, these patients are known to be among those with the highest risk of CRC. There is strong evidence that UDCA has a chemopreventive effect against CRC. However, there is insufficient evidence to determine whether UDCA also has chemopreventive activity in patients with UC who do not have PSC.

Mesalamine compounds have been shown to have a chemopreventive effect in many, but not all, studies. For instance, one meta-analysis demonstrated a preventive effect of mesalamine for CRC (odds ratio, 0.51; 95% CI, 0.37—0.69) and for patients with dysplasia and CRC (odds ratio, 0.51; 95% CI, 0.38—0.69). The benefit occurred with either regular use of mesalamine compounds or by use of at least 1.2 g/day of mesalamine equivalents. In this meta-analysis, use of mesalamine was not significantly associated with a lower risk of dysplasia (odds ratio, 1.18; 95% CI, 0.41—3.43), but only 2 studies evaluated dysplasia as an end point. Most studies have noted that sulfasalazine appears to have a less protective effect compared with mesalamine.

Corticosteroid use has been analyzed in several studies, most of which did not find a chemopreventive effect, although details regarding dose and duration were not available. Two studies reported that systemic corticosteroids, and to a lesser extent topical corticosteroids, resulted in a significant reduction of CRC risk. At this point, chronic corticosteroid use is not recommended solely for the purpose of chemoprevention due to its toxicity.

Little is known regarding the chemopreventive effects of long-term use of immunomodulators (particularly azathioprine and 6-mercaptopurine). However, because these drugs represent the cornerstone of maintenance therapy, their use in clinical practice is not in question. No study, except one, has examined these agents as a primary variable in the assessment of CRC risk in IBD. In the one study that specifically evaluated the efficacy of immunomodulators in reducing the risk of CRC, a protective effect of these agents on the risk of progression to dysplasia or CRC was not detected.

Four studies evaluated folate use in IBD, 2 of which analyzed its use as a primary variable. These studies suggested a trend toward protection against CRC in folate users, but neither study demonstrated statistical significance. No study has specifically analyzed a possible chemopreventive role for calcium, multivitamins, or statins. Thus there is insufficient evidence, either for or against, the use of these agents for prevention of neoplasia in patients with IBD at this time.

Should Molecular Markers Be Applied to Help Stratify Patients Into Low-Risk and High-Risk Groups?

Grade Insufficient: No recommendation; insufficient evidence to recommend for or against the use of molecular markers.

  • Molecular markers should not be applied to help stratify patients into low-risk and high-risk groups at this time.
     

The 3 major molecular pathways of colon carcinogenesis (chromosomal instability, microsatellite instability, and CpG island methylation pathway) also occur in colitis-associated CRC. Much of the data regarding types of molecular alterations in colitis-associated CRC have been obtained from cross-sectional studies that evaluated a particular molecular marker of interest at only one point in time, studying lesions that represent the pathological spectrum of neoplasia (no dysplasia, indefinite for dysplasia, LGD, HGD, and CRC). In these studies, a genetic alteration that demonstrated preferential, or increased, expression in neoplastic tissue was considered a potentially useful marker of neoplasia. However, few markers have been evaluated prospectively, or chronologically, to determine whether they can predict the simultaneous occurrence, or subsequent risk, of dysplasia or CRC. Four tissue-based markers (aneuploidy, p53, microsatellite instability, and the mucin-associated sialyl-Tn antigen) have been evaluated in a chronological context, and each has shown a positive correlation with risk of developing dysplasia or CRC. Of these markers, aneuploidy has been the most thoroughly investigated. Several studies suggest that aneuploidy occurs diffusely throughout the colon and it usually (but not always) either precedes, or develops synchronously with, dysplasia. However, evaluation of aneuploidy by flow cytometry requires considerable technical and professional expertise, which limits its use in routine practice. At this time, there is insufficient evidence to recommend for, or against, the use of any other tissue, serum, or stool-based biomarker in the evaluation of risk of dysplasia or CRC in patients with IBD.

Reference

1Farraye, F.A., Odze, R.D., Eaden, J., and Itzkowitz, S.H. AGA technical review on the diagnosis and management of colorectal neoplasia in inflammatory bowel disease. Gastroenterology. 2010; 138: 746—774

 

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