Inflammatory Bowel Disease and Cancer Risk Goes Beyond the Risk of Colon Cancer

Dr. Rubin of Univ of Chicago discusses improving IBD treatment and the increased risk of cancer in IBD patients.

Inflammatory Bowel Disease and The Risk of Cancer

by Diana Price and Dr. C.H. Weaver M.D. 11/2018

An individual newly diagnosed with inflammatory bowel disease (IBD) will likely go home and immediately type those words into a search engine. Along with information on its causes and treatment, they may encounter what seems like a frightening fact: that the disease brings with it an increased risk of some types of cancer.

For people with IBD, cancer risk “is very much on their radar. It’s one of the things patients fear most, probably only second to the fear of having a permanent ostomy,” says David Rubin MD, co-director of the Digestive Diseases Center at the University of Chicago.

But the good news, adds Dr. Rubin, is that this fear is out of proportion to the actual likelihood that a patient with IBD will develop cancer. And with modern IBD treatments and screening technologies to catch some cancer types early, at a precancerous stage, the risk is now dropping.1

An Inflammatory Environment

With IBD the immune system in the gut is overactive and damages normal tissues. There are two types of IBD: Crohn’s disease and ulcerative colitis. With Crohn’s disease damaging inflammation can occur anywhere along the lining of the digestive tract, from the mouth to the anus. With ulcerative colitis it is mostly confined to the colon and rectum.2

The resulting chronic inflammation can damage the lining of the digestive tract, sometimes severely, leading to the pain, bloating, bowel problems, and bleeding associated with IBD. It can also increase a patient’s risk of cancer through many mechanisms, such as damaging cells’ genetic material and increasing the levels of certain molecules that promote tumor growth.3,4

As one might expect, people with ulcerative colitis or with Crohn’s disease that involves the colon or rectum have an increased risk of colorectal cancer—almost six times higher than people without IBD.

Fortunately, regular screening colonoscopies greatly reduce this risk. “The goal for the prevention of colorectal cancer in patients with IBD, like those without IBD, is to detect it before it gives you symptoms—to find precancerous lesions so that we can intervene [early],” says Dr. Rubin.

In the past this search was complicated by the unusual nature of precancerous growths in people with IBD, explains Dr. Rubin. In people who do not have chronic inflammation in the colon, precancerous growths usually come in the form of polyps; these are small, mushroom-shaped growths protruding from the lining of the intestine, easily seen—and removed—with the endoscopes used for colonoscopy.

But in people with IBD, precancerous growths are often flat lesions that can be hard to distinguish from the intestinal lining. Chronic inflammation can in turn make it more difficult to see these flat lesions.

“Older technologies we had to look at the colon were unable to see most of these lesions,” says Dr. Rubin. “But the field has advanced now, thankfully. We have better technology…and we can see much more than we used to be able to.” This technology includes high-definition digital imaging for endoscopes and contrast dyes that can hide blood vessels and highlight flat precancers.5

Better technology for monitoring precancers has led to a total rethinking of how to manage them, explains Dr. Rubin. In the past doctors would likely remove the entire colon if a precancer was found, for fear that other lesions could be hiding out of sight. “But if you can see the precancerous changes and remove them with the scope, you have the opportunity to follow those patients rather than send them all to surgery and have them lose their colons.” An international consensus statement published in 2015 recommends this more conservative approach.6

In conversations with her patients, Sunanda Kane, MD, MSPH, an IBD specialist at Mayo Clinic Rochester, emphasizes that their increased risk of colorectal cancer is manageable: “Even though you’re at greater risk for colon cancer, there are preventive measures, and they’re very effective.” She also reminds her patients that other ways to reduce the risk of colorectal cancer—like quitting smoking—are completely under their control.

Immunosuppressive Treatment: More Benefits Than Risks

Since 1998 the field of IBD treatment has been revolutionized by the introduction of so-called biologic drugs—drugs designed in the laboratory to attack specific proteins that play a role in disease. Several biologic drugs now approved to treat IBD, including Remicade® (infliximab) and Humira® (adalimumab), target proteins that ramp up the inflammation process.

For many patients these drugs can tamp down inflammation to the point where the lining of the gut has a chance to heal. This can greatly reduce the risk of gastrointestinal cancers.

“The degree of inflammation over time is the single largest independent risk factor for developing precancer or cancer. And the reason that’s an important message for people to understand is the implication—that your disease should be under excellent control to reduce your [cancer] risk,” says Dr. Rubin.

Many patients with IBD, however, come to the clinic having heard that drugs used to treat the disease increase the risk of cancer themselves, making some people reluctant to try effective therapies.

It is true that the immune system can play a role in killing off cancer cells before they grow into full-fledged tumors. Therefore long-term immunosuppression can slightly increase the risk of some cancer types, mainly skin cancer and lymphoma, in people with IBD.7 However, says Dr. Kane, the risk calculations are still firmly in favor of immunosuppressive treatment.

For example, she explains, people with IBD taking immunosuppressive therapies have a fourfold increased risk of lymphoma. She tells her patients that “in the U.S. the [average] risk of developing lymphoma is one in 10,000; so you multiply that by four, and you get four in 10,000. It’s still very unlikely. And the chance of your getting better on the therapy I’m going to give you is 70 percent. So, seven out of 10 people are going to get better, while only four out of 10,000 are going to get a cancer. There’s way more benefit than there is risk,” she asserts.

When biologic drugs for autoimmune diseases targeting a protein called tumor necrosis factor (TNF) first came on the market, researchers expressed concern that they might increase the risk of some solid tumors—and this made it onto the labels of these drugs. But follow-up studies have since minimized this concern.8

“There is no increased risk of solid tumors with anti-TNF therapy,” says Dr. Rubin. “It has been completely disproven in huge numbers of patients and long-term follow-up. But it’s a very common [belief], and it’s misunderstood. Much of the risk initially prescribed to anti-TNF drugs has since been shown to be caused by a much older class of immunosuppressive drugs, called thiopurines, which are not widely used anymore.7,8

“It doesn’t appear that being on [modern] therapy drives cancer risk higher,” adds Dr. Kane. “If anything, therapy decreases your risk because it puts the inflammation under control.”

But Dr. Rubin always reminds his patients who have the disease well under control not to get complacent about cancer screening. “You’re not off the hook,” he says. “Unfortunately, when we finally see cancers in some of these people, a lot of times it’s because they were doing so well that they forgot they even needed [screening] done, and nobody was recommending it.”

Knowing What to Ask For

Sara Ringer has been living with a diagnosis of Crohn’s disease since she was 13, though she likely had the condition since birth. “I was in and out of the hospital since I was a baby, but we couldn’t figure out what was wrong until I was 13,” she recalls.

Two years ago, when she was 32, she got two new diagnoses: precancer of the cervix and several precancerous spots on her skin. Her doctor did mention that her skin precancers may have been due to immunosuppressive treatment. But with her gynecologist who found the cervical precancer, “No conversations took place that ‘this could have happened because you have IBD,’” says Sara.

She found out through her own research that cervical cancer risk may be elevated in women with IBD.9This is also thought to be due to immunosuppression, which makes it harder for the body to fight off infection with human papillomavirus (HPV), the cause of almost all cases of cervical cancer, explains Dr. Rubin. The good news, he adds, is that “this is now considered preventable” with available vaccines against HPV.**

Awareness of risk for cancers outside the colon isn’t very common in people with IBD—or even their doctors. “It’s pretty common to know that risk of colorectal cancer increases, but for others I think there’s a low awareness,” says Sara. “The unfortunate thing is that a lot of patients who have IBD don’t see an IBD specialist—they just have GI doctors, who aren’t as trained as IBD specialists. They may not have time to communicate those risks or even know about them themselves,” she adds.

Sara recommends that individuals with IBD make sure they ask for all the standard cancer screening tests available to them and to monitor things they can see on their own, such as suspicious moles and skin spots. “If their doctor doesn’t bring it up, they should advocate for themselves,” she concludes.

For general information about IBD, see “IBD: Fighting a Fire Within” awomanshealth.com/ibd-fighting-a-fire-within.

Not All Screening Methods Work

Some methods used to screen for colorectal cancer in the general population are not appropriate for people with IBD, explains Dr. Rubin. These include CT colonography, also known as *virtual colonoscopy,*which does a poor job of finding flat precancers. Tests that look for blood in the stool as a sign of early cancer also won’t work because patients with IBD may have blood in their stool due to inflammation.

Rare Gastrointestinal Cancers

People with IBD have an elevated risk of other cancers of the gastrointestinal tract:

  • Small bowel cancer
  • Intestinal lymphoma
  • Anal cancer
  • Bile duct cancer

The amount of increased risk of these cancers can look terrifying out of context. For example, small bowel cancer is almost 30 times as likely to occur in someone with IBD as in the general population; however, reminds Dr. Kane, these cancers are very rare to begin with. “Thirty times rare is still rare,” she says.

Research and The Risk of Cancer in IBD

Thiopurine Treatment for IBD may Increase Leukemia Risk

They are used to reduce inflammation and provide symptom relief. Thiopurine immunosuppressive drugs have been reported to increase the risk of acute myelod leukemia and myelodysplastic syndrome, a rare bone marrow disorder, seven-fold among IBD patients. These data were reported in the medical journal Clinical Gastroenterology and Hepatology.

Common thipurines include azathioprine, 6-mercaptopurine and 6-thioguanin. The researchers conducted a prospective observational study to determine the trends of IBD patients exposed to thiopurines. French researchers studied 19,486 patients enrolled a study between May 2004 and June 2005. After three years of follow up, five patients were diagnosed with myeloid disorders and 4 of these patients had been previously exposed to thiopurines. Patients who were not receiving thiopurines during the study and those who never received these drugs were not found to have an increased risk of myeloid disorders.

These findings raise the concern of a connection between thiopurines and myeloid disorders in IBD patients. The absolute risk to an individual patient however is relatively modest: only 1 in 10,000. Physicians and their patients will need to balance this risk against the known benefits of thiopurines as well as other treatment choices in their overall management of IBD.

Increased Skin Cancer Risk Among Those with IBD

People with IBD may also be at increased risk of non-melanoma skin cancer, particularly if they receive immune-suppressing medications such as thiopurines according to the results of two studies published in Gastroenterology.

Non-melanoma skin cancer refers to skin cancers other than melanoma. The most common types of non-melanoma skin cancer are basal cell carcinoma and squamous cell carcinoma. These types of skin cancer are less likely than melanoma to be fatal (although some deaths do occur), but they can be disfiguring and invade nearby tissues.

Two studies published in the journal Gastroenterology evaluated the risk of non-melanoma skin cancer among people with IBD. The first study involved more than 9,600 IBD patients who had been identified from the University of Manitoba IBD Epidemiology Database. Risk of skin cancer in these patients was compared with the risk in a similar group of people without IBD.[2]

  • People with IBD were 20% more likely to develop basal cell carcinoma than people without IBD.
  • Risk of squamous cell carcinoma was increased among IBD patients who used thiopurines.

The second study was conducted in France and involved more than 19,000 people with IBD. [3]

  • Current and past users of thiopurines had an increased risk of non-melanoma skin cancer. This increased risk was seen even among young patients (those under the age of 50).

These results suggest that people with IBD may have an increased risk of nonmelanoma skin cancer, particularly if they use thiopurines. As a precaution, people with IBD should protect their skin from the sun and monitor their skin for any changes. People with IBD may also wish to talk with their doctor about whether periodic skin exams would be appropriate.

Crohn’s Disease Increases Risk of Intestinal Cancer

According to a combined analysis of six studies, individuals with Crohn’s disease have an increased risk of developing colorectal cancer and small intestine cancer.

In order to evaluate the relationship between Crohn’s disease and risk of colorectal cancer and small intestine cancer, researchers in Sweden conducted a combined analysis of six previously published studies.

The combined analysis suggested that patients with Crohn’s disease had an increased risk of both colorectal cancer and small intestine cancer.

  • The rate of colorectal cancer was almost twice as high in patients with Crohn’s disease than in the general population (90% increased risk).
  • The rate of small intestine cancer was roughly 27-times higher in patients with Crohn’s disease than in the general population.

References:

Jess T, Gamborg M, Matzen P et al. Increased Risk of Intestinal Cancer in Crohn’s Disease: A Meta-Analysis of Population-Based Cohort Studies. American Journal of Gastroenterology. 2005;100:2724-2729.

[1] American Gastroenterological Association. Patient brochure: Inflammatory Bowel Disease. April 23, 2010.

[2] Singh H, Nugent Z, Demers AA, Bernstein CN. Increased risk of nonmelanoma skin cancers among individuals with inflammatory bowel disease. Gastroenterology. 2011;141:1612-20.

[3] Peyrin-Biroulet L, Khosrotehrani K, Carrat F et al. Increased risk for nonmelanoma skin cancers in patients who receive thiopurines for inflammatory bowel disease. Gastroenterology. 2011;141:1621-28.

Lopez et al. Increased Risk of Acute Myeloid Leukemias and Myelodysplastic Syndromes in Patients Who Received Thiopurine Treatment for Inflammatory Bowel Disease. Clinical Gastroenterology and Hepatology 2014: 12(8) 1324-1329.

1 Chapman CG, Rubin DT. The potential for medical therapy to reduce the risk of colorectal cancer and optimize surveillance in inflammatory bowel disease. *Gastrointestinal Endoscopy Clinics of North America,*2014;24(3):353-65. doi: 10.1016/j.giec.2014.03.008.

2 Fakhoury M, Negrulj R, Mooranian A, Al-Sala­mi H. Inflammatory bowel disease: Clinical aspects and treatments. Journal of Inflammation Research. 2014;7:113-20. doi: 10.2147/JIR.S65979.

3 Axelrad JE, Lichtiger S, Yajnik V. Inflammatory bowel disease and cancer: The role of inflammation, immunosuppression, and cancer treatment. World Journal of Gastroenterology. 2016;22(20):4794-801. doi: 10.3748/wjg.v22.i20.4794.

4 Beyaert R, Beaugerie L, Van Assche G, et al. Cancer risk in immune-mediated inflammatory diseases (IMID). Molecular Cancer. 2013;12(1):98. doi: 10.1186/1476-4598-12-98.

5 Bae SI, Kim YS. Colon cancer screening and surveillance in inflammatory bowel disease. Clinical Endoscopy. 2014;47(6):509-15. doi: 10.5946/ce.2014.47.6.509.

6 Laine L, Kaltenbach T, Barkun A, et al. SCENIC international consensus statement on surveillance and management of dysplasia in inflammatory bowel disease. Gastroenterology. 2015;148(3):639-51.e28. doi: 10.1053/j.gastro.2015.01.031.

7 Dulai PS, Siegel CA. The risk of malignancy associated with the use of biological agents in patients with inflammatory bowel disease. Gastroenterology Clinics of North America. 2014;43(3):525-41. doi: 10.1016/j.gtc.2014.05.010.

8 Williams CJM, Peyrin-Biroulet L, Ford AC. Systematic review with meta-analysis: Malignancies with anti-tumour necrosis factor-α therapy in inflammatory bowel disease. Alimentary Pharmacology and Therapeutics. 2014;39(5):447-58. doi: 10.1111/apt.12624.

9 Rungoe C, Simonsen J, Riis L, Frisch M, Langholz E, Jess T. Inflammatory bowel disease and cervical neoplasia: A population-based nationwide cohort study. *Clinical Gastroenterology and Hepatology.*2015;13(4):693-700.e1. doi: 10.1016/j.cgh.2014.07.036.

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