Cancer prevention in patients with IBD

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The Gastroenterology and Endoscopy News US monthly newsletter provided a highly informative article on cancer prevention in patients with inflammatory bowel disease this month…

‘Although gastroenterologists have a solid understanding of the risks of colorectal cancer (CRC) in people with long-standing inflammatory bowel disease (IBD), they face a variety of challenges when choosing the course that is likeliest to prevent CRC in their patients with IBD. The main problem is that no one guideline is recommended for patient surveillance and follow-up; however, understanding which patients are at higher risk for CRC might help gastroenterologists use their resources more effectively.

“The idea is to target your prevention strategies based on an individual patient’s risks. Not every patient has the same risk for dysplasia or cancer,” said David Rubin, MD, at the Great Debates and Updates in Inflammatory Bowel Disease symposium, held in New York City, in April.

“I use the term ‘smart prevention of cancer in IBD’ to individualize risk management, just like you individualize the risks and benefits of therapies,” said Dr. Rubin, who is associate professor of medicine and co-director of the Inflammatory Bowel Disease Center at the University of Chicago Medical Center.

The risk factors for CRC in IBD are well described, the strongest being disease duration. Other key factors include family history of CRC, primary sclerosing cholangitis, younger age at diagnosis and presence of a stricture.

“Several potentially important risk factors include backwash ileitis, presence of pseudopolyps, increased degree of microscopic inflammation and, most importantly I think, lack of medical follow-up and surveillance,” said Sonia Friedman, MD, who also spoke at the symposium. Dr. Friedman is assistant professor of medicine at Harvard Medical School, Brigham and Women’s Hospital, Boston.

Chemoprevention
Dr. Friedman encourages adherence to 5-aminosalicylic acid (5-ASA) therapy for controlling symptoms of IBD as well as for providing potential chemopreventive properties.

“Some literature that says that more than 1.2 g per day of 5-ASAs can help prevent colon cancer, and patients with primary sclerosing cholangitis and ulcerative colitis should be on urso [ursodeoxycholic acid] 300 mg twice a day,” she said.

Indeed, a 2005 meta-analysis found that patients on long-term 5-ASA therapy may reduce their risk for dysplasia or cancer by 50% (Velayos FS et al. Am J Gastroenterol 2005;100:1345-1353). “But there has been some evidence to suggest this is not a chemopreventive therapy,” Dr. Rubin remarked. Older studies failed to control for degree of inflammation, “which you might argue is the most confounding variable.”

In the one study that did account for degree of inflammation, the use of 5-ASAs was not a chemoprotective factor (Rutter M et al. Gastroenterology 2004;126:451-459). Dr. Rubin’s group in Chicago found the chemopreventive quality of 5-ASA borderline and decided that although chemoprevention from 5-ASA is strong in the lab, it may not be significant in a large population.

“I would have to argue there is mixed evidence in the literature,” Dr. Rubin said. “This is something we’re comfortable prescribing because it’s safe and may have some additional efficacy benefits, but the chemopreventive effect of 5-ASA remains unconvincingly proven overall.”

As for urso, a recent study suggests an association between long-term, high-dose urso and an increased risk for colorectal neoplasia in people with primary sclerosing cholangitis and ulcerative colitis (Eaton JE et al. Am J Gastroenterol 2011 May 10 [Epub ahead of print]).

Stratification
Dysplasia is a well-known risk factor for CRC, but not all dysplasia is created equal. It can be helpful to stratify patients and plan a surveillance or intervention strategy based on their type of dysplasia and overall risk factors.

“The concept of stratifying based on the endoscopic appearance and the use of chromoendoscopy has already been incorporated into the British society guidelines, where they allow five years between surveillance colonoscopies if the patient is in deep remission and chromoendoscopy was used,” Dr. Rubin said.

The British approach has not been validated in an evidence-based manner and may require more health care resources, Dr. Rubin noted. But the concept of risk stratification is distinct from a “one-size-fits-all” approach. Factors to consider in risk stratification include grade, morphology, field effect and longitudinal follow-up.

“We appreciate that indefinite dysplasia versus low-grade versus high-grade seem to have some different predictive values,” Dr. Rubin said. “Polypoid, discreet lesions,” as opposed to flat lesions “that are completely resected, … can be followed subsequently in patients, without [requiring] surgery.”

Invisible dysplasia, the kind discovered by accident, “when you’re not looking, or when you’ve done random biopsies, seems to have a worse prognosis,” Dr. Rubin added.

Patients with multifocal dysplasia tend to have a worse prognosis, and patients who have multiple findings over time—those who are followed rather than sent to surgery—also are at higher risk for CRC. Perhaps most concerning, these patients may have advanced CRC when they are diagnosed, so repeated observance of dysplasia is an indicator for surgery.

Surveillance and Screening
Screening colonoscopies should be initiated when ulcerative colitis or Crohn’s disease affects more than one-third of the colon, Dr. Friedman said. From that point, “you’ll want to do a colonoscopy every two years, and after 20 years, every year,” with the exception of patients with primary sclerosing cholangitis, in whom surveillance should begin at the time of diagnosis and be conducted yearly. In patients with left-sided disease, the first screening can wait until 12 to 15 years of disease duration.

Endoscopists are generally encouraged to perform four quadrant biopsies every 10 cm, “but now it’s acceptable to do chromoendoscopy and targeted biopsies,” Dr. Friedman said. Polyps in patients with IBD can be removed because these patients also can get adenomas; physicians often want to repeat the colonoscopy sooner than usual as long as the surrounding tissue is biopsied and is negative for dysplasia, within six to 12 months.

The next issue is how confident the physician is about the dysplasia identified. Dr. Rubin suggests that this confidence varies by grade. Pathologists are good at identifying no dysplasia and high-grade dysplasia or cancer, but identifying indefinite and low-grade dysplasia is murkier. “That’s why it’s recommended that you get a second pathologist to review these [findings] carefully with you.”

The risk for progression from low-grade to higher-grade dysplasia over a five-year period appears to be about 50%, suggesting that surgery might be the preferred course of treatment when low-grade dysplasia is found (Ullman T et al. Gastroenterology 2003;125:1311-1319).
Dr. Rubin also has found the risk for progression to be less than 20% in patients with raised dysplasia that was completely removed. Patients with flat dysplasia appear to have a risk of about 37%.

Location of dysplasia, too, plays a role. Unlike in sporadic or familial CRC, in which right-sided lesions are generally worse, progression to worse dysplasia in patients with ulcerative colitis may be more common with left-sided lesions (Goldstone RN et al. Gastroenterology 2010;138[suppl 1]:S112. Abstract 847h).

“That’s interesting, but it makes sense if you understand that, in colitis, the distal colon has been involved longer and may have been involved with more inflammation in many situations,” Dr. Rubin said. “So again, you stratify your follow-up of patients by understanding their risks based on the location of dysplasia, and by further understanding the differences between right and left colon findings.”

Surgical Intervention
Of course, there is a group of patients who should be considered for surgery instead of followed. These patients may have an unresectable lesion with confirmed dysplasia in it, primary sclerosing cholangitis, uncontrolled inflammation in addition to dysplasia, multifocal dysplasia, psuedopolyps that may conceal dysplasia and possibly left-sided lesions, Dr. Rubin said.
Nonclinical indications for surgery include noncompliance with medical therapy, poor bowel preparation for colonoscopy and resistance to follow up.

“When given the option, one-third of patients might actually prefer colectomy to ongoing further colonoscopy or intensive medical therapy, so keep that in mind,” Dr. Rubin said. He often will send these patients to the surgeon so that they can get a better understanding of what the procedure entails.

“We’re moving toward really understanding individualized risks, and that can be determined based on your patients’ risks as well as the disease, and on lesion-specific risks,” Dr. Rubin said. “I do think we’ve reached the point where some lesions can be followed in a patient if you’re extra careful about doing that,” he concluded.’