Do patients with longstanding inflammatory bowel disease (IBD) have a higher cancer risk than controls? Results from the IBSEN (Inflammatory Bowel South-Eastern Norway) study Ø. Hovde1,2 , M. C. Småsten3,4 , M. L. Høivik4 , B. A.Moum2,4 1Dept. of Gastroenterology, Innlandet Hospital Trust, Gjøvik 2Institute of Clinical Medicine, University of Oslo 3Dept. Of Biostatistics, Faculty of Medicine, University of Oslo 4 Dept. of gastroenterology, Oslo University Hospital, Oslo OSLO Inflammatory Dear chairmen, dear ladies and gentlemen. On behalf of the IBSEN group in Norway it is a great honor and pleasure for me to present our newest data on cancer risk in a well-defined cohort of patients with inflammatory bowel diseases twenty years after diagnosis. The study is population-based, prospective and longitudinal and was performed in four counties in the south-eastern part of Norway. The red areas on the map on the right hand side of the slide show you where the patients and controls live. About 25 % of the Norwegians live in these marked areas. The total population in the marked areas is about one million. Bowel Oslo South East Norway 1 1

Unrestricted grant from Janssen AB and MSD, Norway. To declare: Unrestricted grant from Janssen AB and MSD, Norway. This is the declaration from the authors.

Population. The Inflammatory Bowel South-Eastern Norway (IBSEN) study prospectively followed all patients (n = 756) with ulcerative colitis (UC) and Crohn´s disease (CD). UC and CD: IBD Inclusion period: January 1, 1990 – December 31, 1993. Follow-up: Twenty years. As we all know ulcerative colitis and Crohn´s disease together are called inflammatory bowel diseases, or IBD. 756 IBD patients were followed-up for twenty years and different aspects of the disease progression were been studied.

Background. The incidence and prevalence of IBD is increasing all over the world. It is important to attain reliable data on disease outcome in a well designed , population-based, longitudinal study. In all parts of the world, also in Asia, Africa and South America, the incidence and prevalence of IBD have increased over the past decades. Thus, the total disease burden is increasing. For care-givers, patients and their families it is important to have as much information as possible about the diseases. The best way to retrieve such information is by performing well-designed, population-based, longitudinal studies.

What is IBD-related cancers? Cancers attributable to chronic inflammation and/or to medical treatment of the diseases. Both intestinal and extraintestinal cancers. IBD- related cancers are those cancers related to the diseases in itself or/and to the medical treatment of the diseases. Cancers both within and outside the GI-system might be IBD-related.

We report all cancers diagnosed in IBD patients and their matched controls followed up for 20 years. In the present study all cancers in the IBD group and in the control group were reported.

Aims. Determine the prevalence of intestinal and extraintestinal cancers ( i.e. all cancers) in a well-defined, population-based cohort of IBD patients 20 years after diagnosis. Assess if the IBD patients had an increased cancer-specific risk compared with an age- and gender-matched population. The aims were two-fold: Both to determine the prevalence of intestinal and extraintestinal cancers in a well-defined cohort of IBD patients and to assess if IBD patients had a different cancer-specific risk compared with a gender- and age-matched population.

Methods.   Data on all cancer cases, deaths, causes of death: Collected from the Cancer Registry of Norway and the Cause of Death Registry. Completeness: 98.8 %. Each patient had 25 gender- and age-matched controls from the same geographical area. The Cancer Registry of Norway contains detailed information on each case of cancer. The information about cancer comes from several independent sources, thus securing a completeness at close to 99 %. All medical doctors in Norway have to report new cancers to the Cancer Registry; also in cases where the cancer is first diagnosed at autosy. All Norwegian citizens are given a unique digital ID-number making it possible to link data from several registries, such as the Cause of Death Registry, giving unique possibilities to perform reliable epidemiological research. Every patient had 25 gender- and age- matched controls from the same geographical area.

Characteristics at diagnosis and of use of immunosuppressive drugs/TNF-α inhibitors during the study period.   Crohn´s disease Ulcerative colitis Age, median (range) 28 yr (7-84) 39 yr (4- 89) Gender (females/males) 118/119 252/267 Treated with immunomodulators (azathioprine, methotrexate) (%) 65 (27,1) 34 (6,4) Treated with TNF-α inhibitors (%) 39 (16.5) 12 (2.3) Medical treatment was given in accordance with established clinical practice. During the second half of the study treatment with TNF-α inhibitors with or without concomitant immunomodulators was introduced in the treatment of some of the patients. As you see most of the patients treated with immunomodulators and TNF-α inhibitors were CD patients.

Statistics. All cancers and specific cancer risk for patients compared with controls were modelled using Cox proportional model stratified by matched sets. Results expressed as hazard ratios (HR) with 95 % conficence intervals. P-values < 0.05 considered statistical significant. This is an extract of the statistical methods used in the study.

Results: Over to the results.

Results: 13. 9 % in the IBD group developed cancer. 9.7 % in the control group developed cancer. HR = 1.52, 95 % CI 1.26 – 1.83, p< 0.001. In the diagnosis groups there were no age differences between the genders. Neither the IBD patients nor the controls had been diagnosed with any type of cancer by the start of the study. IBD patients had a higher risk of cancer development than their matched control with a hazard ratio at 1.52.

Male UC patients have an overall increased risk of devloping colo-rectal cancer compared with the controls (HR = 2.54; 95 % CI 1.40- 4.63, p= 0.002). Female UC and CD patients have an increased risk of devloping breast cancer compared with their controls. Male UC patients have an overall increased risk of developing colo-rectal cancer compared with the controls, and both UC and CD patients have an increased risk of developing breast cancer compared with their controls.

Observed and expected numbers of most common malignancies and hazard ratios (HRs) among patients with ulcerative colitis during the whole of the follow-up. Site Observed (n) Expected (n) HR 95 % CI p-value Colon/rectum 14 6.36 2.58 1.49; 4.45 0.001 Trachea/lungs 6 5,52 1.25 0.55; 2.83 0.596 Melanoma 3.2 2.05 0.89; 4.71 0.090 Basal cell carcinoma 5 2.2 2.95 1.18; 7.37 0.021 Breast 13 6.48 2.21 1.26; 3.89 0.006 The hazard ratio for developing CRC is 2.58 with a p-value at 0.001. Noteworthy is the relatively high hazard ratio for breast cancer in the UC-group compared with the controls; also with a low p-value. For basal cell carcinoma HR was 2.95, but with a very wide confidence interval. This result must be interpreted with caution.

Observed and expected numbers of most common malignancies and hazard ratios (HRs) among patients with Crohns´s disease during the whole of the follow-up time. Site Observed (n) Expected (n) HR 95 % CI p-value Colon/rectum 2 2.24 1.09 0.27; 4.48 0.902 Trachea/lungs 5 1.72 3.24 1.28; 8.19 0.013 Melanoma 1 0.8 1.33 0.18; 9.94 0.778 Basal cell carcinoma 0,72 1.65 0.22; 12.36 0.627 Breast 6 2.48 2.59 1.12; 5.98 0.026 Generally there is a higher percentage of smokers and ex-smokers in the CD population than in the general population as well as in the UC population. Our study confirms the increased risk for cancer in the respiratory tract in CD patients, and the main reason for this is thought to be the smokoing habits. And: As you see the risk for breast cancer in CD, as in UC, is found to be increased compared with the controls.

Conclusion: After 20 years with IBD the patients had an overall increased risk of devloping cancer compared with matched controls. Most of the excess risk was comprised by increased risk for colo-rectal cancers in male UC-patients. Breast cancer was over-represented in IBD patients. So: To conclude, ladies and gentlemen: In the IBSEN cohort we found an increased risk of developing cancer compared with gender- and age-matched controls from the same geographical area. Colo-rectal cancers in male UC patients count for much of the difference. Traditionally men are less adherent to medical treatment; might be a part of the picture. In both UC and CD breast cancer was over-represented compared with their matched controls. Even with the high number of patients in this comprehensive prospective follow-up study, the occurrence of cancers seen implied a limited statistical power.

Acknowledgements: We thank the foollowing members of the IBSEN study group: Inger Camilla Solberg, Magne Henriksen, Iril Monstad, Jørgen Jahnsen, Njaal Stray, Ole Høie, Gert Huppertz-Hauss, Tomm Bernklev, Morten Vatn and Johanne Gulbrandsen, The Cancer Registry of Norway. Here is a list of important co-workers who did major contributions in this study.

The IBSEN study group. This is a picture of the extended IBSEN group.

Thank you for your attention! UC patients, especially male, seem to have an increased risk of developing CRC. The fact that breast cancer seem to be more prevalent in IBD patients might, in part, be caused by the fact that an efflux transporter protecting the enterocytes from toxic compounds is found to be down-regulated in patients with active UC and in IBD patients not responding to treatment with 5-ASA and prednisone. Perhaps the inflammatory process is responsible for the reduced levels of this protein (called Breats Cancer Resistance Protein) and hence might be of significance in the pathogenesis of breast cancer?