Inflammatory Bowel Disease and Pancreatic Cancer

A Scandinavian Register-based Cohort Study 1969-2017

Åsa H. Everhov; Rune Erichsen; Michael C. Sachs; Lars Pedersen; Jonas Halfvarson; Johan Askling; Anders Ekbom; Jonas F. Ludvigsson; Henrik Toft Sørensen; Ola Olén

Disclosures

Aliment Pharmacol Ther. 2020;52(1):143-154.

Conclusions

Patients with IBD had an excess risk of pancreatic cancer, especially in those with PSC. However, the cumulative incidence difference after 20 years of follow-up was small (0.05%), that is, one extra case of pancreatic cancer per 2000 IBD patients, which should be reassuring for patients and clinicians alike.

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Funding information
This project was supported by grants from Karolinska Institutet (KI SÖS), Bengt Ihre Research Foundation, Bengt Ihre Research Fellowship, the Swedish Medical Society, the Young Scholar Award from the Strategic Research Area Epidemiology program at Karolinska Institutet, the FORTE foundation, the Swedish Cancer Foundation, The Independent Research Fund Denmark, the Danish Cancer Association, the Novo Nordisk Foundation, and the Regional Agreement on Medical Training and Clinical Research between Stockholm County Council and Karolinska Institutet (ALF). None of the funding organisations had any role in the design and conduct of the study; in the collection, management and analysis of the data; or in the preparation, review and approval of the manuscript.

Acknowledgements
Declaration of personal interests: ÅH Everhov has worked on projects at Karolinska Institutet and SWIBREG partly financed by grants from Ferring and Jansen. JF Ludvigsson coordinates a study on behalf of the Swedish IBD quality register (SWIBREG), which has received funding from Jansen corporation. O Olén has been PI on projects at Karolinska Institutet, partly financed by investigator-initiated grants from Janssen and Ferring, and Karolinska Institutet has received fees for lectures and participation on advisory boards from Janssen, Ferring, Takeda and Pfizer. O Olén also reports a grant from Pfizer in the context of a national safety monitoring program. J Askling acts or has acted PI in agreements between Karolinska Institutet and the following entities, mainly regarding safety monitoring of Rheumatology immunomodulators: Abbvie, AstraZeneca, BMS, Eli Lilly, MSD, Pfizer, Roche, Samsung Bioepis, Sanofi and UCB. J Halfvarson served as speaker and/or advisory board member for AbbVie, Celgene, Celltrion, Dr Falk Pharma and the Falk Foundation, Ferring, Hospira, Janssen, MEDA, Medivir, MSD, Novartis, Olink Proteomics, Pfizer, Prometheus Laboratories, Sandoz, Shire, Takeda, Thermo Fisher Scientific, Tillotts Pharma, Vifor Pharma, UCB and received grant support from Janssen, MSD and Takeda. H T Sørensen, R Erichsen and L Pedersen report that the Department of Clinical Epidemiology, Aarhus University Hospital, receives funding for other studies from companies in the form of research grants to (and administered by) Aarhus University. None of these studies have any relation to the present study.

Authorship
Guarantor of the article
Ola Olén.

Ethical Approval
The study was approved by the regional ethics committee in Stockholm (Dnr 2007/785–31/5, 2011/1509–32, 2014/1287–31/4, 2015/0004–31, 2016/192–31/2) and Danish Data Protection Agency. Since this was a strictly register-based study, individual informed consent was not required^.

Table 1. Characteristics of incident patients with inflammatory bowel disease (IBD) and matched reference population
	Reference	CD	UC	IBD-U
Total	1 599 024 (100)	47 402 (100)	97 514 (100)	17 010 (100)
Denmark	487 984 (30.5)	13 158 (27.8)	33 224 (34.1)	2679 (15.7)
Sweden	1 111 040 (69.5)	34 244 (72.2)	64 290 (65.9)	14 331 (84.3)
Sex
Female	811 203 (50.7)	25 438 (53.7)	47 967 (49.2)	8623 (50.7)
Male	787 821 (49.3)	21 964 (46.3)	49 547 (50.8)	8387 (49.3)
Age at first diagnosis (years)
Median (IQR)	38 (25–56)	34 (23–53)	40 (27–58)	38 (24–58)
<18	149 763 (9.4)	5829 (12.3)	7161 (7.3)	2041 (12.0)
≥18 to <40	699 085 (43.7)	22 058 (46.5)	41 328 (42.4)	7081 (41.6)
≥40 to <60	421 636 (26.4)	11 437 (24.1)	27 239 (27.9)	4033 (23.7)
≥60	328 540 (20.5)	8078 (17.0)	21 786 (22.3)	3855 (22.7)
Year of first IBD diagnosis
2003–2017	731 933 (45.8)	21 056 (44.4)	43 108 (44.2)	9467 (55.7)
1991–2002	524 023 (32.8)	14 729 (31.1)	34 814 (35.7)	3422 (20.1)
1977–1990	283 773 (17.7)	9076 (19.1)	16 671 (17.1)	3336 (19.6)
1969–1976	59 295 (3.7)	2541 (5.4)	2921 (3.0)	785 (4.6)
Age at end of follow-up (years)
Median (IQR)	57 (41–72)	54 (38–69)	58 (43–72)	56 (38–71)
<18	23 399 (1.5)	1000 (2.1)	941 (1.0)	405 (2.4)
≥18 to <40	368 624 (23.1)	12 377 (26.1)	20 148 (20.7)	4439 (26.1)
≥40 to <60	496 828 (31.1)	14 827 (31.3)	31 461 (32.3)	4711 (27.7)
≥60	710 173 (44.4)	19 198 (40.5)	44 964 (46.1)	7455 (43.8)
Length of follow-up (years)
≥0 to <1	83 429 (5.2)	3149 (6.6)	6329 (6.5)	1277 (7.5)
≥1 to <5	316 655 (19.8)	8973 (18.9)	19 406 (19.9)	4219 (24.8)
≥5 to <10	353 859 (22.1)	9705 (20.5)	21 509 (22.1)	4275 (25.1)
≥10 to <20	539 141 (33.7)	15 059 (31.8)	34 249 (35.1)	4419 (26.0)
≥20	305 940 (19.1)	10 516 (22.2)	16 021 (16.4)	2820 (16.6)
Excluding the first year of follow-up	1 515 595 (94.8)	44 253 (93.4)	91 185 (93.5)	15 733 (92.5)
Primary sclerosing cholangitis
At or during follow-up	NA	645 (1.4)	2381 (2.4)	453 (2.7)
Before start of follow-up	NA	137 (0.3)	605 (0.6)	112 (0.7)
Duration < 5 years	NA	356 (0.8)	1110 (1.1)	260 (1.5)
Duration 5 to <10 years	NA	211 (0.4)	671 (0.7)	142 (0.8)
Duration ≥10 years	NA	215 (0.5)	1205 (1.2)	163 (1.0)

Table 2. Incidence rates and standardised rates for pancreatic cancer per 100 000 person years overall and by inflammatory bowel disease subtype
	All inflammatory bowel disease		Crohn's disease		Ulcerative colitis
	Patients	Reference	Patients	Reference	Patients	Reference
N total	161 926	1 599 023	47 402	468 066	97 514	963 240
N events	442	3386	116	907	270	2146
Cumulative 10-year incidence (%)	0.18 (0.16–0.20)	0.14 (0.13–0.15)	0.16 (0.12–0.20)	0.10 (0.09–0.11)	0.18 (0.15–0.21).	0.16 (0.15–0.17)
Difference (95% CI)	0.04 (0.02–0.06)	—	0.06 (0.02–0.10)	—	0.02 (−0.01 to 0.05)	—
Cumulative 20-year incidence	0.34 (0.30–0.38)	0.29 (0.28–0.30)	0.29 (0.22–0.35)	0.24 (0.22–0.26)	0.35 (0.30–0.40)	0.31 (0.30–0.33)
Difference (95% CI)	0.05 (0.01–0.09)	—	0.04 (−0.02 to 0.11)	—	0.04 (−0.02 to 0.09)	—
Incidence proportion (percent)	0.27	0.21	0.24	0.19	0.28	0.22
Person years	2 000 951	20 402 533	633 267	6 481 193	1 174 621	11 915 981
Incidence rate (95% CI)	22.1 (20.1–24.2)	16.6 (16.0–17.2)	18.3 (15.3–22.0)	14.0 (13.1–14.9)	23.0 (20.4–25.9)	18.0 (17.3–18.8)
Standardised^a incidence rate—Overall	9.04 (8.15–9.93)	7.02 (6.77–7.26)	9.30 (7.49–11.12)	7.05 (6.57–7.53)	8.58 (7.51–9.65)	7.08 (6.77–7.39)
Standardised^a incidence rate—Female	7.78 (6.66–8.90)	6.56 (6.25–6.88)	9.19 (6.84–11.54)	6.74 (6.13–7.35)	6.65 (5.35–7.96)	6.56 (6.15–6.98)
Standardised^a incidence rate—Male	10.47 (9.05–11.89)	7.53 (7.15–7.91)	9.47 (6.57–12.38)	7.46 (6.69–8.24)	10.66 (8.91–12.41)	7.61 (7.14–8.07)

^aIncidence rates standardised to the Nordic population in the year 2000.

Table 3. Incidence rates (per 100 000 person years) and hazard ratios for pancreatic cancer in patients with inflammatory bowel disease and matched reference population
	Incidence rate in cases N events, IR (95% CI)	Incidence rate in reference N events, IR (95% CI)	Hazard ratio (95% CI)
Total	442, 22.1 (20.1–24.2)	3386, 16.6 (16.0–17.2)	1.43 (1.30–1.58)
Denmark	177, 36.3 (31.3–42.1)	1276, 25.6 (24.3–27.1)	1.53 (1.30–1.79)
Sweden	265, 17.5 (15.5–19.8)	2110, 13.7 (13.1–14.3)	1.38 (1.21–1.56)
Crohn's disease	116, 18.3 (15.3–22.0)	907, 14.0 (13.1–14.9)	1.44 (1.18–1.74)
Ulcerative colitis	270, 23.0 (20.4–25.9)	2146, 18.0 (17.3–18.8)	1.35 (1.19–1.53)
IBD unclassified	56, 29.0 (22.3–37.7)	333, 16.6 (14.9–18.5)	1.99 (1.50–2.64)
Sex
Female	198, 19.4 (16.9–22.3)	1696, 16.3 (15.5–17.0)	1.30 (1.12–1.50)
Male	244, 24.9 (22.0–28.2)	1690, 17.0 (16.2–17.8)	1.56 (1.37–1.79)
Age at first IBD diagnosis (years)
<18	6, 2.69 (1.21–5.99)	22, 0.99 (0.65–1.50)	2.78 (1.13–6.86)
18 to <40	94, 9.18 (7.50–11.2)	576, 5.64 (5.20–6.12)	1.68 (1.35–2.09)
40 to <60	168, 32.3 (27.8–37.6)	1310, 24.6 (23.3–26.0)	1.34 (1.14–1.57)
≥60	174, 74.1 (63.9–86.0)	1478, 55.9 (53.1–58.8)	1.33 (1.14–1.56)
Year of first diagnosis
2003–2017	89, 20.6 (16.8–25.4)	636, 14.6 (13.5–15.8)	1.51 (1.21–1.89)
1990–2002	164, 21.0 (18.0–24.4)	1350, 17.0 (16.1–17.9)	1.33 (1.13–1.57)
1977–1989	146, 24.1 (20.5–28.4)	1049, 16.9 (15.9–18.0)	1.54 (1.29–1.83)
1969–1976	43, 23.6 (17.5–31.9)	351, 18.4 (16.6–20.4)	1.37 (1.00–1.88)
Years of follow-up
0 to <1	58, 37.2 (28.8–48.1)	216, 13.9 (12.1–15.9)	2.73 (2.05–3.65)
1 to <5	94, 13.6 (11.1–16.7)	760, 11.0 (10.2–11.8)	1.31 (1.06–1.62)
5 to <10	90, 8.22 (6.69–10.1)	779, 7.03 (6.55–7.54)	1.26 (1.01–1.57)
10 to <20	108, 7.88 (6.52–9.51)	993, 7.10 (6.67–7.56)	1.22 (1.00–1.48)
≥20	92, 10.8 (8.80–13.2)	638, 7.15 (6.62–7.73)	1.66 (1.33–2.07)
Excluding the first year after diagnosis	384, 20.8 (18.8–23.0)	3170, 16.8 (16.2–17.4)	1.34 (1.20–1.48)
Primary sclerosing cholangitis
At or during follow-up	34, 92.1 (65.8–129)	61, 14.3 (11.1–18.4)	7.55 (4.94–11.5)
Duration < 5 years	21, 128 (83.3–196)	19, 11.0 (7.01–17.2)	12.0 (6.42–22.3)
Duration ≥5 to <10 years	8, 77.5 (38.7–155)	11, 9.40 (5.21–17.0)	10.1 (4.06–25.3)
Duration ≥ 10 years	5, 49.2 (20.5–118)	31, 22.7 (16.0–32.3)	2.83 (1.09–7.32)