A total of 33 905 patients in the GPRD population had received a 5-ASA prescription: 18 969 were assigned to the “5-ASA/IBD” group (56 patients with a history of CRC prior to the first recorded ASA prescription were excluded). Mean age of these patients was 48 years and 53.0% were women. They were followed for an average of six years. Their average number of 5-ASA prescriptions during follow up was 19.4 (median 10); these were prescribed for an average of one month of treatment. The distribution of the type of prescribed 5-ASA in the “5-ASA/IBD” group was as follows: mesalazine (57.9%), sulfasalazine (37.2%), olsalazine (4.6%), and balsalazide (0.4%). The “sulfasalazine/RA” cohort consisted of 14 840 patients (40 patients excluded because of CRC history). Each of these patients was matched to one patient without a record of IBD or 5-ASA use.
The incidence rate in the “5-ASA/IBD” group was 0.17 CRC cases per 100 patients per year in this cohort (table 1).
Table 1 Incidence rates of colorectal cancer (CRC) in the different study cohorts (number of cases per 100 patients per year)
The rate in the reference cohort (that is, patients without IBD and 5-ASA use) was 0.09 (the age and sex adjusted RR in the “5-ASA/IBD” cohort compared with the reference cohort was 1.99 (95% confidence interval (CI) 1.54–2.56). The CRC risk of patients in the “sulfasalazine/RA” group was comparable with that of the reference patients.
Among the 124 CRC cases in the “5-ASA/IBD” group, the most frequent CRC locations (based on the codes used by the general practitioner and/or general practitioner comments recorded in the record) concerned the colon (43 patients), rectum (39), sigmoid (5), rectosigmoid (5), descending colon (1), transverse colon (3), ascending colon (1), and caecum (18). There were nine patients with unspecified bowel carcinoma. All-cause mortality was high among CRC cases in all groups: the one year life table mortality in the “5-ASA/IBD” group was 35.8% (five year 63.7%); this was 41.8% (61.7%) for the cases in the “sulfasalazine/RA” group and 41.3% (63.7%) for the cases in the reference group, respectively. The most frequently recorded cause of death among the CRC cases in the “5-ASA/IBD” group was carcinoma (91.9%). Of the 124 CRC cases in the “5-ASA/IBD” group, 100 were current users of 5-ASA drugs (that is, received a prescription in the six months before). These cases were matched to 600 controls: 96.0% of the cases were matched by year of birth, sex, and calendar time (and 98.2% were matched within five years of age).
In this population, significant risk factors for CRC included history of colon/rectum polyps (crude OR 10.24 (95% CI 3.42–30.69)) and number of general practitioner visits for IBD symptoms (one symptom 1.24 (95% CI 0.74–2.06); two or more symptoms 2.70 (95% CI 1.45–5.04)) (table 2).
Table 2 Characteristics of colorectal cases and controls
Current use of NSAIDs was associated with a reduced risk of CRC but this did not reach statistical significance (OR 0.80 (95% CI 0.38–1.66)). Duration and type of IBD also predicted the risk of CRC (table 3).
Table 3 Risk of colorectal cancer (CRC) and type and duration of inflammatory bowel disease (IBD)
Patients with UC had higher a CRC risk compared with patients with CD (OR 2.86 (95% CI 1.22–6.72)). In both CD and UC, longer disease duration increased the risk of CRC.
Table 4 shows the risks of CRC according to regularity of 5-ASA use.
Table 4 Regular 5-aminosalicylate (5-ASA) use in the year before and risk of colorectal cancer (CRC)
Patients who were regular 5-ASA users in the year preceding the index date had a decreased risk of CRC compared with irregular users (crude OR 0.67 (95% CI 0.44–1.03); adjusted OR 0.60 (95% CI 0.38–0.96)). Similar reductions in CRC risk were seen when looking at 5-ASA use in the 1–2 years prior to the index date. Regular users of mesalazine appeared to have larger CRC risk reductions than regular users of sulfasalazine but IBD duration was longer among users of sulfasalazine compared with mesalazine (average of 14 and 6 years, respectively). When stratified by disease type, regular 5-ASA users with UC had an adjusted OR for cancer of 0.65 (95% CI 0.37–1.14) compared with irregular users. For CD, numbers were small but regular users had an adjusted OR of 1.66 (0.29–9.52) compared with irregular 5-ASA users.
Among the control patients, regular and irregular users were statistically comparable with respect to prior IBD duration, one year mortality, and number of general practitioner records and barium examinations/colonoscopies in the 6–24 months before (both for regular users in the year before and in the 1–2 years before);
Among 5-ASA users who also had used oral glucocorticoids or immunosuppressants in the six months before, there were no differences in risk of CRC between regular and irregular 5-ASA users (adjusted OR 1.21 (95% CI 0.43–3.45)). In contrast, regular 5-ASA use was associated with a reduced risk of CRC in non-users of oral glucocorticoids or immunosuppressants (adjusted OR 0.53 (95% CI 0.30–0.92)). A separate case control analysis was conducted to compare regular and irregular users of oral glucocorticoids or immunosuppressants with IBD. Among users of these anti-inflammatory drugs, regular use was also associated with a reduced risk of CRC compared with irregular use (crude OR 0.51 (95% CI 0.27–0.98); adjusted OR 0.38 (95% 0.18–0.80)). In patients with RA with current use of sulfasalazine, there were no differences in the risk of CRC between regular and irregular users (crude OR 1.00 (95% CI 0.38–2.64)). However, the number of cases was small (n
Additional analyses were conducted to evaluate the robustness of the findings. Restriction of the analysis to cases (n
74) and controls (n
401) with >2 years of retrospective information prior to the index date yielded comparable results (adjusted OR for regular use in the year before of 0.60 (95% CI 0.35–1.06) and 0.57 (95% CI 0.28–1.16) for regular use in the 1–2 years before. An analysis excluding 5-ASA users who only received one 5-ASA prescription yielded an adjusted OR of 0.68 (95% CI 0.42–1.11) for regular use in the year before. Medical records were also reviewed for general practitioner visits for CRC symptoms prior to the index date and an analysis was conducted using this revised index date: the adjusted OR for regular use in the year before of 0.63 (95% CI 0.39–1.01) and 0.49 (95% CI 0.24–0.98) for regular use in the 1–2 years before. An analysis including all 124 CRC cases found that CRC risk was reduced in patients using 5-ASA regularly compared with irregular/non-users (adjusted OR was 0.68 (95% CI 0.44–1.06) for regular 5-ASA use in the one year before, and 0.57 (95% CI 0.36–0.90) for regular use in the 12–24 months before).
We also sent a questionnaire to general practitioners to confirm the CRC diagnosis of 23 cases (the number of cases available for validation was limited due to large numbers of patients who had died; the notes are no longer available for these patients). Twenty returned questionnaires were analysed: the diagnosis of CRC was confirmed by the general practitioner in all of these cases. IBD location was provided in 14 cases: pancolitis UC six, rectum only UC three, descending colon UC two, caecum only UC one, beyond splenic flexure but not pancolitis UC one, and colon and small bowel CD one patient.