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IBD Therapy Cancer Risks and How to Counsel Patients
Damian McNamara
December 12, 2015
ORLANDO — People with inflammatory bowel disease (IBD) treated with certain biologic and immunomodulator therapies face increased risk for some cancers, data show, with risks varying by patient age, sex, and other factors.
Counseling patients about the benefits of these therapies while discussing the relative risk for malignancies can inform educated treatment decisions, said presenters speaking here at the Crohn's and Colitis Foundation of America Advances in Inflammatory Bowel Diseases (AIBD) Conference.
"We're going to be seeing questions rising from this more and more over time," Thomas Ullman, MD, from Mount Sinai Medical Center in New York City, said. "We need to have an open and honest discussion with patients before starting [therapy]."
Specific Agents and Specific Risks
Physicians can start off the conversation with some good news: Published studies do not suggest these therapies predispose patients with IBD to all kinds of cancers going forward. In fact, in a systemic review and meta-analysis (Aliment Pharmacol Ther. 2014;39:447-458), and in a national registry study in Denmark (JAMA. 2014;311:2406-2413), the overall cancer risk was not elevated.
"With cancer, we are really talking about many different diseases," Dr Ullman said. "We would like to separate these out when we can."
Researchers are doing just that. The greatest risks appear to be for development of lymphoma, nonmelanoma skin cancer, or urinary tract cancers, depending on patient demographics and the agent prescribed. Some published reports also point to an increase in cervical malignancies, although the evidence so far remains mixed, Dr Ullman said.
Lymphoma
A transplant-like lymphoma is the most common form of lymphoma that develops in patients with IBD treated with thiopurines. The incidence is as high as 1 in 1000 patient years, Dr Ullman said. Less common but just as worrisome is a postmononucleosis lymphoma that develops in 0.1 per 1000 patient years. This form tends to affect men, especially those younger than 35 years. A third and even less common form, hepatosplenic T-cell lymphoma, also tends to strike younger men. The rate is 0.05 per 1000 patient years, and it tends to develop after at least 2 years of therapy with a combination of thiopurines and anti-tumor necrosis factor treatment or thiopurines alone.
One agent in this class, azathioprine, was associated with a 2.40 increased lymphoma risk in a study published in the American Journal of Epidemiology (2013;177:1296-1305). Other researchers report risks elevated between two and four times in patients with IBD treated with this agent, Dr Ullman said.
"So it's certainly something we have to be conscious of when we prescribe these medications."
To help minimize risks for patients, Dr Ullman recommends checking Epstein-Barr virus status in men younger than 35 years, minimizing thiopurine exposure to 2 years or less in the same subpopulation, and considering prescription of methotrexate instead of thiopurines in high-risk patients.
The combination of azathioprine and 6-mercaptopurine carries a 4.92 times elevated risk for lymphoma development in the IBD population, according to a meta-analysis published in Clinical Gastroenterology and Hepatology (2015;13:847-858). In this study, men younger than 30 years were at increased risk, as were men older than 50 years (who carried the highest absolute risk, at 4.78).
"Make this a shared decision with your patients and try not to freak them out by talking in absolute numbers. Risk for lymphoma is small, and five times a small number is still small," Dr Ullman said. "But also talk about the benefits of treatment."
Lymphoma risk returns to near baseline after stopping thiopurines, the same meta-analysis indicates. "It's quite impressive that three- to fourfold risk comes down to one to two," Dr Ullman said. "That's certainly encouraging news."
Skin Cancers
Unlike lymphoma, the risk for nonmelanoma skin cancers does not appear to drop to near baseline in patients after treatment cessation. Ongoing treatment with thiopurines was associated with a hazard ratio of 5.9 for nonmelanoma skin cancers in a study published in Gastroenterology (2011;14:1621-1628). Previous thiopurine use was also associated with increased risk (hazard ratio, 3.9).
Methotrexate may also increase the risk among people with IBD and rheumatoid arthritis with a history of nonmelanoma skin cancers, according to a study published in JAMA Dermatology (Published online October 28, 2015. doi:10.1001/jamadermatol.2015.3029). Risk for subsequent nonmelanoma skin cancers carried hazard ratios of 1.24 for methotrexate alone and 1.49 for methotrexate in combination with other anti-tumor necrosis factor agents.
"To our surprise, there was a very clear signal that methotrexate increased the risk of nonmelanoma skin cancer compared to not taking methotrexate," James D. Lewis, MD, from the University of Pennsylvania School of Medicine in Philadelphia, said.
"There is a bit of a question on melanoma, and a more certain risk with nonmelanoma skin cancers," Dr Ullman said. For example, one study showed a 1.8 times increased risk for melanoma among people with IBD treated with biologics ( Gastroenterology. 2012;143:390-399). Although the risk appears lower, "it's enough that we want to consider our patients for being at risk for melanoma going forward."
Dr Ullman recommends that gastroenterologists send any patients with IBD at higher risk for skin cancer to a dermatologist for an annual full skin examination, and to counsel patients about ultraviolet light exposure and use of sunscreen.
Urinary Tract Cancers
Cancers of the urinary tract were almost three times more likely (hazard ratio, 2.82) among patients with IBD treated with thiopurines compared with those not treated with these agents in a study published in Alimentary Pharmacology and Therapeutics (Published online November 9, 2015. doi: 10.1111/apt.13466).
The researchers note clinically relevant elevated risks among older men in the study. "Keep this in mind when we're seeing our patients," said Dr Ullman.
Cervical Dysplasia
Immune suppression with IBD is a potential risk factor for cervical cancer, Dr Ullman said, but there are "mixed findings in the literature, and not a lot of consistency." Nevertheless, he added, this is a disease with a great screening tool available. "Make sure patients have Pap testing twice in the first year on thiopurines, and get [human papillomavirus] vaccination early on."
Keeping Risks in Perspective
"Malignancies are a common concern for both doctors and patients looking at these treatments," session moderator Bruce E. Sands, MD, from Mount Sinai Medical Center in New York City told Medscape Medical News.
"The risks are there, and they're very important for everyone to understand. But in absolute terms, they're small," he said. Because the risks do not appear the same for all people with IBD, he added that physicians are starting to risk-stratify patients by age and sex.
Dr Ullman agreed. "In many situations, and in most of the literature, it's very small numbers of events that drive these seemingly scary relative risk ratios or hazard ratios. I think we need to keep that in mind."
Dr Ullman is a consultant for Janssen and received a grant from Genentech. Dr Lewis disclosed relationships with Bayer, Merck, Nestle Health Science, Pfizer, and Takeda. Dr Sands disclosed relationships with AbbVie, Avaxia Biologics, Bristol Myers Squibb, Celgene, Janssen, ETX Pharma, MedImmune, Pfizer, Prometheus, Rockpointe, Salix, Shire, Takeda, and UCB.
