1Department of Epidemiology Research, National Health Surveillance & Research, Ørestads Boulevard 5, DK-2300 Copenhagen S, Denmark *Author for correspondence: Tel.: +45 32 68 37 22; [email protected]
It is generally accepted that both ulcerative colitis (UC) and colonic Crohn’s disease (CD) are associated with an increased risk of colorectal cancer (CRC) [1], but the magnitude of the risk is subject to debate and may have changed over time. Previous reports of severely ill patients referred to tertiary centers suggested a markedly increased risk of CRC in UC, as reflected in a meta-analysis by Eaden and colleagues published in 2001 [2]. The meta-analysis was based on both referral center populations, surgical series, surveillance programs, population-based cohorts and histology series and reported a cumulative risk of CRC in UC of 2, 8 and 18% after 10, 20 and 30 years, respectively. However, acknowledging that only prognostic data from an unselected patient population (representing the whole spectrum of disease) apply to the average inflammatory bowel disease (IBD) patient, a new meta-analysis was conducted in 2012 [3]. It revealed a 2.4-fold increased risk of CRC in patients with UC, estimated from eight population-based studies covering the
time period from 1954 to 2004. However, despite the 2.4-fold increased relative risk, the absolute risk of CRC was only 1.6% overall after 7–24 years (mean: 14 years) of follow-up, with a cumulative probability of CRC of less than 1% at 10 years, 0.4–2% at 15 years and 1.1–5.3% at 20 years follow-up. Notably, these numbers also included sporadic cases of CRC.
In addition to a limited absolute risk of CRC in UC, one has to consider the marked changes in the management of IBD over the past 30–40 years. These changes include altered use and type of diagnostics and surgery; increased use of medical therapy, with a shift from the era of sulfasalazine, 5-aminosalicylic acid and corticosteroid treatment to the era of immunomodulatory agents, such as thiopurines; and TNF antagonists. Studies on 5-aminosalicylic acid use and risk of CRC have failed to show a chemopreventive effect [4], whereas thiopurines have recently been suggested to reduce the risk of CRC among patients with IBD [5]. Most likely,
“...the absolute risk of colorectal cancer in inflammatory bowel
disease is limited and a marked decrease in both risk of colorectal
cancer and mortality from colorectal cancer has been
observed among patients with ulcerative colitis...”
EDITORIAL
“The risk of intestinal malignancy in Crohn’s disease
varies worldwide and only limited data are available.”
Important changes in the pattern of colorectal cancer in patients with inflammatory bowel disease
the risk of CRC in IBD decreases with enhanced control of inflammation, whether this is done by given medications, close follow-up and early treatment of flares or surgery [6].
A Swedish study published in 2009, based on the Uppsala cohort, the Stockholm cohort and the Stockholm pancolitis register, found a tendency towards decreased risk of CRC and a significant decrease in CRC mortality within the IBD population covering an almost 40-year time period [7]. Specifically, when comparing IBD patients with the background population, the relative risk of CRC ranged from 5.4 in the oldest cohort to 1.8 in the newest (2000–2004) cohort; and cumulative estimates of CRC at 10, 20 and 30 years after IBD diagnosis were 1, 1.5 and 2.7% [7].
A recent nationwide Danish study covering almost the same time period concluded that the overall risk of CRC among Danish patients with UC did not differ from that of persons without IBD and, most importantly, that the relative risk of CRC had decreased significantly over time from 1.16 (95% CI: 0.87–1.55) among patients diagnosed with UC in 1979–1988 to 0.59 (95% CI: 0.39–0.90) among patients diagnosed with UC in 1999–2008 [8]. The lack of an overall increase in risk of CRC among UC patients in the study by Jess et al. [8] is in accordance with results from a former unselected cohort study from Copenhagen County [9], and with other recent European studies reporting no increase or only a moderately increased risk of CRC in UC [10–12]. Whether the observed decrease in risk of CRC in UC over time is due to improved management of UC with better control of colonic inflammation or due to changes in UC phenotypes over time remains to be investigated.
The risk of intestinal malignancy in CD varies worldwide and only limited data are available. A number of studies have suggested an increased risk of CRC among patients with CD [13–15] whereas other studies have failed to confirm such an association [16–18]. However, as for UC, the
selected nature of former studies and potential changes over time need to be considered. A meta-analysis of six population-based studies of CRC in CD revealed an increased standardized incidence ratio of 2.5 (95% CI: 1.7–3.5), and a particularly high risk in patients with colonic CD (standardized incidence ratio: 4.3; 95% CI: 2.0–9.4)[19]. However, the studies included in the meta-analysis were quite old (covering the period 1940–2002), and updated population-based studies are few in number. The recent 15-year follow-up of the EC-IBD cohort showed no increased risk of CRC in UC and CD combined [12], whereas the recent nationwide Danish study of CRC in IBD showed no decrease in risk of CRC in patients with CD over time but also no increased overall risk [8]. Neither study has shown the risk of dying from CRC to have decreased during the last three decades, in contrast to what was suggested in the Swedish study covering IBD overall [7].
In summary, the absolute risk of CRC in IBD is limited and a marked decrease in both risk of CRC and mortality from CRC has been observed among patients with UC in recent years. The reason for this phenomenon is still to be explained, but could potentially reflect improved control of inflammation with new treatment options. Interestingly, the decrease in risk of CRC in UC has not been paralleled with a similar decrease in patients with CD, potentially indicating that there is still a need for better control of colonic inflammation in this patient group.
Financial & competing interests disclosureThe authors have no relevant affiliations or financial involvement with any organization or entity with a finan-cial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert t estimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.
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Important changes in the pattern of colorectal cancer in patients with inflammatory bowel disease Editorial
