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Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgement
  8. References

Background  Crohn's disease is associated with small bowel cancer whilst risk of colorectal cancer is less clear.

Aim  To ascertain the combined estimates of relative risk of these cancers in Crohn's disease.

Methods  MEDLINE was searched to identify relevant papers. Exploding references identified additional publications. When two papers reviewed the same cohort, the later study was used.

Results  Meta-analysis showed overall colorectal cancer relative risk in Crohn's disease as 2.5 (1.3–4.7), 4.5 (1.3–14.9) for patients with colonic disease and 1.1 (0.8–1.5) in ileal disease. Meta-regression showed reduction in relative risk over the past 30 years. Subgroup analysis showed Scandinavia had significantly lower colorectal cancer relative risk than the UK and North America. Cumulative risk analysis showed 10 years following diagnosis of Crohn's disease relative risk of colorectal cancer is 2.9% (1.5%–5.3%). Meta-analysis showed small bowel cancer relative risk in Crohn's disease is 33.2 (15.9–60.9). Small bowel cancer relative risk has not significantly reduced over the last 30 years.

Conclusion  Relative risk of colorectal and small bowel cancers are significantly raised in Crohn's disease. Cumulative risk of colorectal cancer of 2.9% at 10 years suggests a potential benefit from routine screening. However, the value of screening requires rigorous appraisal.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgement
  8. References

Prevalence and incidence rates of Crohn's disease have been increasing in both the US1–3 and Europe.4–6 A recent study in the UK using primary care data reported a prevalence as high as 145 cases per 100 000.7 Prevalence of Crohn's disease in North America is currently estimated between 26 and 199 cases per 100 000, which means there are as many as 600 000 patients with Crohn's disease in North America alone.8

An association between colorectal cancer and ulcerative colitis was first reported in 1925.9 Many studies have looked at the link between these diseases as well as risk factors that might increase the likelihood of an individual with ulcerative colitis developing cancer. Meta-analysis of these papers found that the risk of colorectal cancer for a patient with ulcerative colitis is 2% at 10 years, 12% at 20 years and 18% at 30 years disease duration.10 In contrast, there have been fewer studies on the link between Crohn's disease and cancer, with most focusing on small bowel and colorectal cancers, the first report being that of an adenocarcinoma of the ascending colon in 1948.11

There is a strong association between Crohn's disease and developing cancer of the small bowel, with relative risks (RRs) reported of between 3.412 and 85.513 compared to the general population. Small bowel cancer is rare, accounting for only 1–5% of all gastrointestinal malignancies,14 so the absolute risk remains small. It is, however, less clear if there is an increase in the RR of developing colorectal cancer in patients with Crohn's disease, reports vary from 0.815 to 20.0.16

This systematic review and meta-analysis of published data aims to provide an accurate overview of the current risk of colorectal and small bowel cancer in Crohn's disease. An accurate analysis of these data will help establish the likely risk of developing cancer for patients with Crohn's disease and so enable patients to make informed choices with regard to treatment and inform the debate regarding surveillance and screening for colorectal cancer in patients with Crohn's disease.

Methods

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgement
  8. References

Search strategy

Published reports calculating the risk of cancer in Crohn's disease were identified through a literature search of MEDLINE using the following key words, both in free text and as MESH headings: Crohn's disease, inflammatory bowel disease, cancer, neoplasm. A comprehensive search of reference lists of all review articles and original studies retrieved by this method was performed to identify additional reports. Through this approach 544 papers were identified that had been published between 1972 and 2004.

Inclusion and exclusion criteria

Only English language journal papers were included where Crohn's disease patients had been studied and statistics regarding risk of cancer calculated that included either RR (incidence risk ratio compared to the general population) or reported observed and expected cancers. Studies were excluded if they only reported occurrence of cancer as case studies, with regard to surgical technique, histology, diagnostic techniques, possible biochemical pathways or as part of a randomized control trial for a drug. When two or more publications from one institution appeared to review the same patients only the most recent study results were included. This left 14 original papers for the analyses, 12 reporting colorectal cancer risk and eight reporting small bowel cancer risk (Figure 1).

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Figure 1. The Quality of Reporting of Meta-analyses (QUOROM) statement flow diagram17 indicating the inclusion and exclusion criteria for papers into this meta-analysis.

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Data extraction

Each paper was critically reviewed and the following data were extracted:

  • 1
    country of origin;
  • 2
    type of centre where study was conducted;
  • 3
    duration of study;
  • 4
    mean follow up of patients (patient years exposure);
  • 5
    number of patients in the study;
  • 6
    mean duration of disease in study participants;
  • 7
    the RR of colorectal cancer or small bowel cancer;
  • 8
    the confidence interval for RRs or observed and expected numbers of colorectal and small bowel cancers;
  • 9
    median year of diagnosis of patients.

Study details are summarized in Table 1. Community-based studies are ones in which a population of patients with Crohn's disease lived or were diagnosed in a defined geographic area, whilst hospital or specialist centre-based studies include patients referred to the institute from an undefined area. All studies are limited by bias27 but this can be reduced if six standards are met.27 These include appropriate and accurate case definition, high level of patient follow up, clear statement of outcomes measured, number of years over which the study was conducted, the centre where it was conducted and number of patients included. Studies conducted over a long period with a large population and long follow up with few patients lost represent better quality and the results would be more reliable. All papers included within this analysis reported on a population studied for at least 10 years and followed patients for a mean duration of at least 8.5 years.

Table 1.  Details of study and study population
Paper (including country of origin and year)Median year of diagnosis with Crohn'sDuration of study (years)Mean duration of follow up (years)Centre where study was conductedStudy population size
Fielding18 1972 – UK19533013.8Hospital295
Weedon16 1973 – US19425315.8Hospital449
Gyde19 1980 – UK19613214.5Hospital513
Greenstein13 1981 – US19711611.0Hospital579
Kvist20 1986 – Denmark197319 9.0Specialist referral centre473
Gollop21 1988 – US196150 9.2Community based103
Fireman22 1989 – Israel19751010.0Community based365
Ekbom12 1990 – Sweden19741811.5Hospital1655
Gillen23 1994 – UK196030 2.0Hospital281
Persson15 1994 – Sweden196929No appropriate data recordedCommunity based1251
Mellemkjaer24 2000 – Denmark198312 9.6Hospital2645
Bernstein25 2001 – Canada199013 7.5Community based2857
Jess26 2004 - Denmark19742517Specialist referral centre374

Statistical analysis

All analyses were performed using STATA statistical software (College Station, TX, USA). The overall pooled estimate and 95% confidence interval of RR of colorectal and small bowel cancers were obtained separately for patients with Crohn's disease using either a fixed or random effects meta-analysis model on a log RR scale as appropriate depending on a test for heterogeneity using a 10% significance level.28 Heterogeneity in the log RR over time was explored using random effects meta-regression for both cancer types. The weight given to studies is inversely proportional to the variance associated with the RR reported in each. For the studies where the confidence interval was not reported, standard error was calculated using the observed cancers and expected cancers reported in the papers. The data used in both meta-analyses are summarized in Table 2. Heterogeneity was explored using meta-regression techniques to assess any change in RR of cancer with time, and subgroup analysis was used to explore differences due to site of initial Crohn's disease, country and type of centre in which study was undertaken, these data are included in Table 1. Sensitivity analyses were undertaken to explore the influence on the overall results of individual studies.

Table 2.  Study data used in the meta-analyses of colorectal cancer and small bowel cancer risk in Crohn's disease
AuthorRRUpper CILower CIlog RRSE [log RR]
  1. * Confidence intervals calculated using observed and expected data, rather than being directly extracted.

  2. RR, relative risk.

Colorectal cancer
 Weedon et al.1620.08.634.43.00.35
 Gyde et al.184.32.08.21.50.3
 Greenstein et al.136.92.814.21.90.38
 Kvist et al.20*2.11.03.30.760.58
 Gollop et al.21*2.00.043.70.701.0
 Fireman et al.22*0.40.012.3−0.201.0
 Ekbom et al.122.51.34.30.920.29
 Gillen et al.233.41.56.71.20.35
 Persson et al.150.840.271.9−0.200.45
 Mellemkjaer et al.241.10.601.90.100.26
 Bernstein et al.252.61.74.10.970.76
 Jess et al.261.10.132.90.130.50
Small bowel cancer
 Fielding et al.1810010198.6124.60.71
 Greenstein et al.1385.886.884.8244.50.50
 Ekbom et al.123.40.1018.61.21.0
 Gillen et al.2340.041.438.63.70.71
 Persson et al.1515.64.340.12.80.50
 Mellemkjaer et al.2417.95.842.02.90.45
 Bernstein et al.2517.44.22.92.90.73
 Jess et al.2666.718.11714.20.50

The pooled estimate for RR of colorectal cancer in patients with Crohn's disease was then used in a cumulative probability analysis, using the national annual incidence in the UK reported by the National Institute for Clinical Excellence,29 to calculate the risk of developing colorectal cancer over 30 years diagnosed with Crohn's disease, assuming a constant annual incidence ratio. This was then compared to the cumulative risk in the general population29 and in patients with ulcerative colitis.30

Results

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgement
  8. References

Colorectal cancer

Two of the 12 papers in this study reported a RR less than 1.015, 22 and four further papers reported a confidence interval that included 1.0.20, 21, 24, 26 The risk reported in the remaining papers ranged from 2.512 to 20.0.16 A chi-squared test for heterogeneity based on these 12 studies yielded χ2 = 66.904, P < 0.00001 and therefore a random effects model was used to produce an overall pooled estimate for the colorectal cancer RR of 2.5 with a 95% confidence interval 1.3–4.7, which was statistically significant (P = 0.004; Figure 2). Subgroup analysis was carried out for colorectal cancer specific to the site of the Crohn's disease, colonic disease or ileal disease. Five papers specified colorectal cancer incidence in patients with colonic disease,12, 15, 19, 23, 26 the overall pooled estimate for RR of colorectal cancer in these patients is 4.5 with a 95% confidence interval 1.3–14.9, which was statistically significant (P < 0.015; Figure 3). Only three papers specify the incidence of colorectal cancer in patients with ileal disease,12, 15, 26 the combined RR for these patients is 1.1 with 95% confidence interval 0.8–1.5, this risk is not statistically significantly greater than the risk of the general population (P = 0.7). Subgroup analysis was also carried out for the geographical region in which the study was conducted. This showed RR of colorectal cancer in Scandinavia is not significantly higher than seen in the general population, 1.4 (0.9–2.2); whilst in the UK and North America risk it is significantly higher, with RR 3.9 (2.4–6.2) and 8.5 (2.9–24.7) respectively. Subgroup analysis of the type of centre where the study was conducted showed no significant difference in RR reported from primary, secondary or tertiary centres. When change in RR with time, assessed by taking the median year of diagnosis plus the average follow-up time, was assessed using a mixed effects meta-regression model there was a decrease in RR of 0.09 each year (95% confidence interval −0.12 to −0.06) this was statistically significant (P = 0.016).

image

Figure 2. Forest plot of studies reporting relative risk (RR) of colorectal cancer (log scale) for Crohn's patients.

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image

Figure 3. Forest plot of studies reporting relative risk (RR) of colorectal cancer (log scale) for patients with Crohn's disease located in the colon.

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The cumulative risk analysis for all patients with Crohn's disease at any site showed that the incidence of colorectal cancer in patients diagnosed with Crohn's disease for 10 years is 2.9% (1.5–5.3%), 5.6% (3.1–10.4%) for patients who have been diagnosed for 20 years and 8.3% (4.5–15.1%) for those diagnosed for 30 years. Cumulative risk of developing colorectal cancer once diagnosed with Crohn's disease is compared to risk in ulcerative colitis30 and the general population29 in Figure 4 and this shows that the risk of colorectal cancer for patients with Crohn's disease is statistically significantly greater than in the general population and not statistically significantly different to the risk for patients with ulcerative colitis.

image

Figure 4. Cumulative risk of colorectal cancer in patients diagnosed with Crohn's disease (solid black line with dark grey 95% confidence interval) compared to that seen in ulcerative colitis, based on unstratified data (black and white dot and dashed line with light grey 95% confidence interval) and the cumulative risk in the general population (dashed line, no confidence interval).

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Sensitivity analysis shows the study by Weedon et al.16 has the single greatest effect on the combined RR. However, omitting this study reduces the combined RR estimate to 2.1 (95% CI 1.4–3.3), which remains within the 95% confidence interval of the overall estimate for all studies. Excluding Weedon et al.16 from the meta-regression of change in colorectal cancer risk with time results in the decrease being no longer statistically significant, −0.029 (95% CI −0.074 to 0.017, P = 0.21). If Weedon et al.16 is removed from the sub-group analysis of country, then RR for North America is reduced to 3.8 (95% CI 1.8–8.3).

Small bowel cancer

Only eight papers were found that reported RR for small bowel cancer in Crohn's disease. All report the risk as increased from that in the general population, ranging from 3.412 to 10018 and none report confidence intervals that include 1.0. A chi-squared test for heterogeneity based on these studies yielded χ2 = 18.196, P < 0.011 and therefore a random effects model was used to produce an overall pooled estimate for small bowel cancer RR of 31.2 (95% CI 15.9–60.9), which is highly statistically significant (P < 0.0001; Figure 5). Subgroup analysis was carried out for the geographic region in which the study was conducted. This showed that the RR of small bowel cancer in Scandinavia was again lower than in the UK and US, but on this occasion the difference was not significant and was still much higher than in the general population. RR by geographic region was: 19.4 (7.4–50.8), 63.3 (23.7–168.5) and 44.2 (8.9–199.7) for Scandinavia, the UK and North America respectively. Subgroup analysis of the type of centre where the study was conducted, again showed no significant difference in RR reported from primary, secondary or tertiary centres. When change in RR with time, assessed by median year of diagnosis plus the average follow-up time, was assessed using a mixed effects meta-regression model there was no significant change.

image

Figure 5. Forest plot of studies reporting relative risk (RR) of small bowel cancer (log scale) for Crohn's patients.

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Discussion

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgement
  8. References

This study shows the overall combined risk of colorectal cancer in Crohn's disease is more than two and a half times that of the general population. For patients with colonic disease this risk is increased to almost four and a half times that of the general population. From the data available, the risk of colorectal cancer in patients with isolated ileal disease is not statistically significantly different to the general population, although data on colorectal cancer risk in patients with ileal Crohn's disease is very limited. The study by Weedon et al.16 has the single greatest effect on the combined RR, reporting an especially high RR. However, only patients diagnosed before the age of 21 were included, a patient group known to be at greater risk of colorectal cancer.12, 23 The other studies have less individual effect on the combined RR, showing the result of the meta-analysis is robust. The percentage weight of each study in the meta-analysis was around 10% except the studies by Gollop21 and Fireman22 which contributed 5.5% each.

Patients with Crohn's disease in the UK have a significantly higher RR of colorectal cancer than those in Scandinavia. The UK is less pro-active in its approach to surgery than Scandinavia31 and this could explain the difference. A meta-analysis of international mortality for patients with Crohn's disease32 shows that mortality for patients with Crohn's disease is not significantly different in these countries, so it would seem the difference in colorectal cancer incidence does not affect overall mortality. In Scandinavia patients with Crohn's disease are managed in specialist referral centres whilst in the UK care is mainly given within the community with occasional hospital support.33 This difference in approach does not appear to be important, however, as subgroup analysis showed no significant difference between RR of colorectal cancer reported from different types of healthcare setting.

Meta-regression analysis of change in RR of colorectal cancer over time shows risk has decreased from 1940 to 1990, but if the study by Weedon et al.16 is excluded this decrease is no longer statistically significant. Whilst the introduction of steroids and azathioprine may have lowered mortality32 they have not reduced the risk of developing colorectal cancer, suggesting that these drugs modify some aspects of Crohn's disease but do not affect the pathology that underlies development of colorectal cancer. Some recent studies have reported that whilst acute inflammation counteracts cancer development, chronic inflammation, as in Crohn's disease, promotes cancer in three main ways.

  • 1
    Tumour necrosis factor binding to the NFKappaB receptor promotes survival signalling to the cell, which is pro-oncogenic.34
  • 2
    IL-6 counteracts apoptosis of cells.33
  • 3
    COX-2 is elevated in both chronic inflammation and carcinogenesis. Raised expression is associated with poor prognosis in colorectal adenocarcinoma when inhibited tumour growth is suppressed.35

Infliximab is an anti-tumour necrosis factor antibody, so it may modify the disease in a way that reduces colorectal cancer risk. In the US 20% of colorectal cancer is linked to smoking36 and a high proportion of Crohn's patients smoke,37, 38 which represents an additional risk factor.

Patients with ulcerative colitis are known to have an increased RR of developing colorectal cancer with a cumulative probability of 3% at 10 years.10 It is recommended that such patients are screened for dysplasia of the colonic mucosa by colonoscopy 10 years after diagnosis and repeated every 2 years.39, 40 The cumulative risk of colorectal cancer 10 years after diagnosis of Crohn's disease at any site is 2.9% and Figure 4 shows no significant difference in risk of colorectal cancer between patients with ulcerative colitis and Crohn's disease, implying that patients with Crohn's disease at any site should be offered the same screening opportunities as those with ulcerative colitis, the results of the subgroup analysis would suggest that this is even more important in patients with colonic involvement. There are many studies of colorectal cancer risk in ulcerative colitis that stratify data by duration of disease. This has allowed more accurate assessment of risk over time, with 18% cumulative probability after 30 years. Similar analysis is not possible with current papers in Crohn's disease because there are too few that stratify risk of developing colorectal cancer at different durations of disease, but it is possible that cumulative risk will increase in a similar way. The benefit of screening has yet to be established. Indeed it has been suggested that rather than increasing survival following diagnosis, screening only increases the lead time39 and a recent paper on cost efficacy reports that for biannual screening to be cost effective in ulcerative colitis the risk must be greater than 27%.41 Even after 30 years the risk of colorectal cancer in ulcerative colitis is only 18%, so it would seem guidelines for screening for colorectal cancer in inflammatory bowel disease need revision.

The pooled estimate from the meta-analysis of small bowel cancer risk showed an overall RR of 31.2 compared to the general population. Whilst this is very high, the real risk is small because small bowel cancer is rare and accounts for less than 5% of all gastrointestinal cancers.14 There are currently no effective methods to screen for small bowel cancer and the low incidence, even in Crohn's disease, means there is no possibility of screening. This may change, however, with the increasing use of capsule endoscopy. There is no statistically significant difference in risk of small bowel cancer between different countries or study centres, neither is there any statistically significant change in risk of small bowel cancer in Crohn's disease over 45 years, using median year of diagnosis with Crohn's disease as the marker for passage of time. This would further suggest that steroids and azathioprine have not modified the pathological process that increases the risk of intestinal cancer.

There are few papers reporting RR of colorectal or small bowel cancer in Crohn's disease, far less than there are for ulcerative colitis and this limits this meta-analysis. Whilst the papers reporting RR of small bowel cancer report similar findings, the results of studies into RR of colorectal cancer vary greatly, thus there is a considerable uncertainty for the true value of RR. It is unlikely that the true risk of colorectal or small bowel cancer in Crohn's disease has been reported as a capture–recapture technique was not used in any study and no studies had an average follow up exceeding 20 years, with most less than 15 years. Also as there is no screening programme for small bowel cancer some asymptomatic patients would not have been identified. Further investigation via an individual patient detail meta-analysis is required to fully elucidate the colorectal and small bowel cancer risks experienced by patients with Crohn's disease and utilize individual patient covariates.

Acknowledgement

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgement
  8. References

The study was sponsored by the University of Leicester NHS Trust.

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgement
  8. References
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