Inflammatory bowel disease in children increases cancer risk

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Children diagnosed with inflammatory bowel disease have an increased risk of cancer, especially gastrointestinal cancers, both in childhood and later in life, finds a study led by researchers at the Karolinska Institute in Sweden. The increase persists into adulthood, and has not fallen since the introduction of modern drug therapies for inflammatory bowel disease. However, the researchers stress that absolute risks are low – corresponding to one extra case of cancer for every 556 patients with inflammatory bowel disease followed for a year, compared with healthy individuals.

Inflammatory bowel disease (IBD) is a term used to describe two conditions that involve inflammation of the gut: ulcerative colitis and Crohn’s disease. People of any age can get IBD, but it’s usually diagnosed between the ages of 15 and 40.

Previous studies have identified higher rates of cancer among patients with IBD than the general population, but these studies have lacked the population size or follow-up to assess trends in lifetime risks in childhood onset IBD.

So the team of international researchers set out to assess the risk of cancer in patients with childhood onset inflammatory bowel disease in childhood and adulthood. They compared 9,405 people living in Sweden who were diagnosed with inflammatory bowel disease before they were 18 years of age with 92,870 healthy individuals (reference individuals) matched for sex, age, birth year, and place of residence.

They analysed risk of cancer before 18th birthday, 25th birthday, and throughout the study period (1964 to 2014) up to an average age of 30 years.

After taking account of potentially influential factors, the researchers found 497 first cancers in patients with childhood onset inflammatory bowel disease (3.3 per 1000 person years), compared with 2,256 cancers in matched individuals (1.5 per 1000 person years). This corresponds to one extra case of cancer for every 556 patients with inflammatory bowel disease monitored for a year, compared with reference individuals. Risks were increased in the first year after diagnosis and remained high beyond five years of follow-up, especially for gastrointestinal cancers (colorectal, small intestinal and liver cancer). Chronic liver disease, longstanding colitis, and a family history of early cancer were risk factors for any cancer in childhood onset inflammatory bowel disease.

The study was not big enough to recognise whether drugs were also a risk factor. Instead, the authors suggest that “extent and duration of chronic inflammation might be the main driving mechanisms underlying the increased risk of cancer.”

The authors point out that this is an observational study, so no firm conclusions can be drawn about cause and effect, and they outline some limitations that could have introduced bias. However, strengths include the large number of participants and virtually complete follow up.

They conclude: “Childhood onset inflammatory bowel disease is associated with an increased risk of any cancer, especially gastrointestinal cancers, both during childhood and later in life. The higher risk of cancer has not fallen over time.”

In a linked editorial, Professor Susan Hutfless at Johns Hopkins University, says this is a “thoughtful and thorough investigation” that “confirms the need for international collaboration in the study of cancer surveillance for these children.”

She urges families “to focus on the very low incidence of cancer in childhood” and calls for international efforts to confirm these findings and extend their reach to the increasing number of children diagnosed as having inflammatory bowel disease globally. This, she says, will “help improve decision making for the many patients and their families who must choose between different options for both treatment and surveillance.”

Abstract
Objective: To assess risk of cancer in patients with childhood onset inflammatory bowel disease in childhood and adulthood.
Design: Cohort study with matched general population reference individuals using multivariable Cox regression to estimate hazard ratios.
Setting: Swedish national patient register (both inpatient and non-primary outpatient care) 1964-2014.
Participants: Incident cases of childhood onset (<18 years) inflammatory bowel disease (n=9405: ulcerative colitis, n=4648; Crohn’s disease, n=3768; unclassified, n=989) compared with 92 870 comparators from the general population matched for sex, age, birth year, and county.
Main outcome measures: Any cancer and cancer types according to the Swedish Cancer Register.
Results: During follow-up through adulthood (median age at end of follow-up 27 years), 497 (3.3 per 1000 person years) people with childhood onset inflammatory bowel disease had first cancers, compared with 2256 (1.5 per 1000 person years) in the general population comparators (hazard ratio 2.2, 95% confidence interval 2.0 to 2.5). Hazard ratios for any cancer were 2.6 in ulcerative colitis (2.3 to 3.0) and 1.7 in Crohn’s disease (1.5 to 2.1). Patients also had an increased risk of cancer before their 18th birthday (2.7, 1.6 to 4.4; 20 cancers in 9405 patients, 0.6 per1000 person years). Gastrointestinal cancers had the highest relative risks, with a hazard ratio of 18.0 (14.4 to 22.7) corresponding to 202 cancers in patients with inflammatory bowel disease. The increased risk of cancer (before 25th birthday) was similar over time (1964-1989: 1.6, 1.0 to 2.4; 1990-2001: 2.3, 1.5 to 3.3); 2002-06: 2.9, 1.9 to 4.2; 2007-14: 2.2, 1.1 to 4.2).
Conclusion: Childhood onset inflammatory bowel disease is associated with an increased risk of any cancer, especially gastrointestinal cancers, both in childhood and later in life. The higher risk of cancer has not fallen over time.

Authors
O Olén, J Askling, MC Sachs, P Frumento, M Neovius, KE Smedby, A Ekbom, P Malmborg, JF Ludvigsson

BMJ material
BMJ abstract


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