Alimentary Pharmacology and Therapeutics

Systematic review with meta-analysis: the declining risk of colorectal cancer in ulcerative colitis C. Casta~ no-Milla*,†, M. Chaparro*,† & J. P. Gisbert*,†

*Gastroenterology Unit, Hospital Universitario de La Princesa, Instituto de Investigaci on Sanitaria Princesa (IP), Madrid, Spain. † Centro de Investigaci on Biomedica en Red de Enfermedades Hepaticas y Digestivas (CIBEREHD), Madrid, Spain.

Correspondence to: Dr C. Casta~ no-Milla, Ram on G omez de la Serna 5, 5ºB, 28035 Madrid, Spain. E-mail: [email protected]

Publication data Submitted 20 June 2013 First decision 19 July 2013 Resubmitted 18 January 2014 Accepted 18 January 2014 EV Pub Online 9 February 2014 As part of AP&T’s peer-review process, a technical check of this meta-analysis was performed by Mr M. Siddiqui. This article was accepted for publication after full peer-review.

SUMMARY Background Patients with ulcerative colitis (UC) have an increased risk of developing colorectal cancer (CRC); however, the magnitude of this effect is open to debate. Aim To assess the risk of CRC in UC patients by systematic review and metaanalysis. Methods A systematic literature search was performed up to November 2013. We selected studies describing the incidence and prevalence of CRC in patients with UC. Articles were assessed for quality using the Newcastle-Ottawa Scale. Cumulative incidence and incidence rates of CRC were combined and analysed using the generic inverse variance method. Sub-analyses were performed to identify factors associated with an increased risk of developing CRC. Results A total of 81 studies (181 923 patients) met the inclusion criteria. The incidence rate of CRC in patients with UC was 1.58 per 1000 patient-years (py) [95% confidence interval (CI), 1.39–1.76]. Results were heterogeneous (I2 = 81–89%). The incidence rate was 4.02/1000 py (95%CI = 2.74–5.31) in studies that only included patients with extensive colitis, and 1.24/1000 py (95%CI = 1.01–1.47) in population-based studies. The incidence rate was 0.91/1000 py (95%CI = 0.61–1.2) in the first decade of disease, 4.07/1000 py (95%CI = 2.58–5.56) in the second, and 4.55/1000 py (95%CI = 2.64–6.46) in the third. The incidence rate decreased from 4.29/1000 py in the studies published in the 1950s to 1.21/1000 py in studies published in the last decade. Conclusions The risk of patients with ulcerative colitis developing colorectal cancer has decreased steadily over the last six decades, but the extent and duration of the disease increase this risk. Aliment Pharmacol Ther 2014; 39: 645–659

ª 2014 John Wiley & Sons Ltd doi:10.1111/apt.12651

645

~o-Milla et al. C. Castan INTRODUCTION The inflammatory bowel diseases (IBD), ulcerative colitis (UC) and Crohn’s disease have been associated with an increased risk of developing colorectal cancer (CRC), probably caused by long-standing chronic inflammation.1 However, the magnitude of this effect remains open to debate. In 2001, Eaden et al. published a landmark meta-analysis, reporting that the cumulative risk of CRC in patients with UC was 2% at 10 years, 8% at 20 years and 18% at 30 years.2 This meta-analysis and other studies showed that the risk of developing CRC in UC patients is increased by specific factors, such as disease duration, extensive mucosal involvement, concomitant primary sclerosing cholangitis,3–5 a family history of CRC6 and early onset of UC.7, 8 These results were the basis for the current guidelines on endoscopic surveillance of CRC in UC patients.9–11 However, recent studies have reported the incidence of CRC to be considerably lower. The aim of the present systematic review and meta-analysis was to update the estimation of the incidence of CRC in patients with UC. METHODS The present systematic review and meta-analysis was presented according to the PRISMA statement.12 PRISMA checklist can be found in supplementary information as Appendix S1. Search strategy for identification of studies To collect all published reports describing the incidence and prevalence of CRC in UC, we performed a search of the MEDLINE, EMBASE, CINAHL and Cochrane Collaboration databases without language restrictions and up to November 2013 using the following strategy: (‘colorectal cancer’ OR ‘colon cancer’ OR ‘dysplasia’) AND (‘ulcerative colitis’ OR ‘inflammatory bowel disease’). The reference lists of all the articles included were scrutinised to disclose additional literature on the topic. Study selection criteria We included all articles describing cohorts of UC patients that provided the incidence rate of CRC and follow-up time, as well as those with enough information for calculating these data. The diagnosis of UC was based on well-defined and internationally accepted criteria.13–17 Studies that did not provide the criteria for diagnosis of UC were noted in Table 1. Studies reporting information on IBD without specific data for UC patients or follow-up were excluded. Diagnosis of CRC was based on 646

appropriate clinical, endoscopic, histopathological and radiological findings, but histopathological lesions diagnosed as dysplasia were considered separately. If duplicate publications on a given cohort were identified, only the publication with longest follow-up was included.

Data extraction Data were extracted independently by two reviewers (C.C. and M.C.). Discrepancies in interpretation were resolved by consensus. For each study included, we retrieved data on the number of patients, country where it was performed, year of publication, design, mean or median follow-up, extension of disease, colectomy rate, number of observed colorectal cancer cases and age at diagnosis of UC and CRC and at the beginning of follow-up. Quality of assessment Investigators assessed the methodological quality of every included study by Newcastle-Ottawa quality assessment scale (NOS) for cohort studies, which contains 9 items. The NOS assigns a maximum of 4 points for selection, a maximum of 2 points for comparability, and a maximum of 3 points for exposure/outcome (Appendix S2). Therefore, 9 points is the highest score, reflecting the highest quality.18 Statistical analysis When possible, the actual number of cases of CRC observed and the duration of follow-up [patient-years (py)] were extracted. When only the number of cases and duration of the follow-up were provided, the incidence risk was calculated. Cumulative incidence and incidence rates were calculated for each paper with the corresponding 95% confidence intervals (CIs). Cumulative incidence was defined as the probability of developing a CRC per 1000 UC patients during the whole follow-up. Incidence rate was defined as the number of new CRC cases diagnosed per 1000 py. Heterogeneity was assessed using the v2 test for each combined analysis, where P < 0.1 indicated significant heterogeneity between studies.19 We reported the I2 statistic, which calculates the percentage of total variation across studies that is due to heterogeneity (an approach that has recently been endorsed by the Cochrane Collaboration). We defined significant heterogeneity as I2 > 25%, based on the judgment that I2 values of 25%, 50% and 75% represent low, moderate and high heterogeneity respectively.20 In cases of high heterogeneity, we further investigated the source using techniques such as Aliment Pharmacol Ther 2014; 39: 645-659 ª 2014 John Wiley & Sons Ltd

Systematic review with meta-analysis: risk of colorectal cancer in ulcerative colitis Table 1 | Study characteristics Type of study

Design of study

Definition of UC

Follow-up since diagnosis

Screening interventions

Frequency of interventions

Referral centre Referral centre Referral centre Referral centre Referral centre Referral centre

Retrospective

NS

No

Proctoscopy

NS

Retrospective

NS

No

Colectomies

NS

Retrospective

NS

No

Sigmoidoscopy

NS

Retrospective

NS

No

NS

Retrospective

NS

No

Proctosigmoidoscopy and barium x-ray Barium x-ray

Retrospective

NS

No

NS

Referral centre Referral centre Referral centre Referral centre

Retrospective

NS

No

Sigmoidoscopy and barium x-ray NS

Retrospective

NS

No

NS

Retrospective

NS

No

Sigmoidoscopy or necropsy Interview

Retrospective

LJC

No

Sigmoidoscopy and barium x-ray Colonoscopy and barium x-ray Sigmoidoscopy and barium x-ray Colectomies

Every year since start of the study Repeated, but NS

Sigmoidoscopy and barium x-ray Sigmoidoscopy and barium x-ray NS

NS

Author

Year

Country

Flood23

1956

USA

Thorlakson24

1956

UK

Banks25

1957

USA

Dennis26

1961

USA

Russell27

1961

Australia

Hijmans28

1962

USA

Korelitz29

1962

USA

Edwards30

1964

UK

MacDougall31

1964

UK

De Dombal32

1966

UK

Aktan33

1970

Turkey

Referral centre

Retrospective

NS

No

Gilat34

1974

Israel

Referral centre

Retrospective

EAC

Yes

Baker35

1978

UK

Retrospective

NS

No

Kewenter36

1978

Sweden

Referral centre Cohorts

Retrospective

NS

No

Lanfranchi37

1980

Italy

Referral centre

Retrospective

NS

No

Prior38

1982

UK

Retrospective

NS

No

Johnson39

1983

Australia

Referral centre Referral centre

Prospective

NS

No

Katzka40

1983

USA

Retrospective

NS

Hendriksen41

1985

Denmark

Retrospective

Maratka42

1985

Czech Republic

Referral centre Populationbased Referral centre

Mirmadjlessi43 Mirmadjlessi44

1985 1986

Iran USA

Gilat45

1988

Gyde46

1988

NS

NS

Every year

NS

NS

Repeated, but NS NS NS

No

Sigmoidoscopy and barium x-ray Colonoscopies

NS

Yes

NS

NS

Retrospective

NS

Yes

NS

Referral centre Referral centre

Retrospective Retrospective

NS NS

No Yes

Israel

Referral centre

Retrospective

NS

Yes

UK

Cohorts

Retrospective

NS

Yes

Colonoscopy and barium x-ray NS Colonoscopy and barium x-ray Colonoscopy and barium x-ray Colonoscopy and barium x-ray

Aliment Pharmacol Ther 2014; 39: 645-659 ª 2014 John Wiley & Sons Ltd

NS

NS NS

NS

NS

647

~o-Milla et al. C. Castan Table 1 | (Continued) Design of study

Definition of UC

Follow-up since diagnosis

Author

Year

Country

Type of study

Rutegard47

1988

Sweden

Population-based

Retrospective

NS

No

Kvist48

1989

Denmark

Referral centre

Retrospective

NS

No

Lashner49

1989

USA

Referral centre

Prospective

NS

Yes

Lennard-Jones50

1989

UK

Referral centre

Retrospective

NS

Yes

Colonoscopy and barium x-ray

Lofberg51

1990

Sweden

Referral centre

Prospective

NS

No

Colonoscopy

Lynch52

1993

UK

Referral centre

Prospective

NS

No

Colonoscopy

Connell53

1994

UK

Referral centre

Prospective

NS

No

Colonoscopy

Jonsson54

1994

Sweden

Referral centre

Prospective

NS

No

Colonoscopy

Lashner55

1995

USA

Retrospective

NS

No

Colonoscopy

Mellemkjaer56

1995

Denmark

Retrospective

Colonoscopy

NS

1995

Israel

Prospective

ICD-8 code for UC NS

No

Rozen57

Referral centre Populationbased Referral centre

Every year after 8 years from diagnosis Every 2 years after 10 years from diagnosis Every 2 years after 8 years from diagnosis Every year after 8 years from diagnosis Every 2 years after 10 years from diagnosis Every 2 years after 10 years from diagnosis in left-sided colitis and annually in extensive colitis NS

No

Colonoscopy

Stewenius58 Radhakrishnan59

1995 1997

Sweden Oman

Cohorts Referral centre

Prospective Retrospective

EAC NS

Yes Yes

Colonoscopy Colonoscopy

Triantafillidis60

1998

Greece

Retrospective

LJC

Yes

Colonoscopy

Karlen61

1999

Sweden

Retrospective

NS

No

Colonoscopy

NS

Palli62

2000

Italy

Referral centre Populationbased Referral centre

Every 1–3 years after 7 years from diagnosis NS Every year after 10 years from diagnosis NS

Retrospective

NS

No

NS

Wandall63 Askling64

2000 2001

Denmark Sweden

Retrospective Retrospective

BC LJC

Yes Yes

Bernstein65

2001

USA

Cohorts Populationbased Cohorts

Colonoscopy and barium x-ray Colonoscopy Colonoscopy

Prospective

ICD-9 code for UC

No

Colonoscopy

NS

648

Screening interventions

Frequency of interventions

Colonoscopy and barium x-ray Colonoscopy and barium x-ray Colonoscopy

NS

NS

NS NS

Aliment Pharmacol Ther 2014; 39: 645-659 ª 2014 John Wiley & Sons Ltd

Systematic review with meta-analysis: risk of colorectal cancer in ulcerative colitis Table 1 | (Continued) Design of study

Definition of UC

Follow-up since diagnosis

Screening interventions

Frequency of interventions Every 2 years after 10 years from diagnosis NS Every 2 years or yearly after 7 years from diagnosis NS

Author

Year

Country

Type of study

Lindberg66

2001

Sweden

Cohorts

Prospective

NS

Yes

Colonoscopy

Viscido67 Biasco68

2001 2002

Italy Italy

Cohorts Referral centre

Prospective Prospective

NS NS

Yes Yes

NS Colonoscopy

Al-Shamali69

2002

Irak

Retrospective

NS

No

Colonoscopy

Hata70

2003

Japan

Referral centre Cohorts

Prospective

NS

Yes

Colonoscopy

Winther71

2004

Denmark

Retrospective

NS

Yes

Colonoscopy

Katsanos72

2005

Greece

Retrospective

NS

No

Colonoscopy

NS

Khorrami73

2005

Spain

Populationbased Referral centre Referral centre

Every year after 7 years from diagnosis NS

Prospective

LJC

No

Colonoscopy

Lindberg74

2005

Sweden

Cohorts

Prospective

NS

Yes

Colonoscopy

Venkataraman75

2005

India

Referral centre

Retrospective

NS

Yes

Colonoscopy

Jess76

2006

USA

Populationbased

Retrospective

LSC

Yes

Colonoscopy

Lakatos77

2006

Hungary

Cohorts

Retrospective

LJC

No

Colonoscopy

Rutter78

2006

UK

Referral centre

Prospective

NS

Yes

Colonoscopy

Ghazzawi79

2007

Jordan

Referral centre

Retrospective

LJC

No

Jess80 Goldacre81

2007 2008

Denmark UK

Cohorts Cohorts

Retrospective Retrospective

Yes No

Chow82

2009

China

Cohorts

Prospective

NS ICD-9 code for UC LJC

Colonoscopy and barium x-ray Colonoscopy NS

Every 2 years after 8 years from diagnosis Every 2 years after 6 years from diagnosis in extensive colitis and every 2 years after 10 years from diagnosis in left-sided colitis Every year after 7 years from diagnosis Every 2 years or yearly after 7–10 years rom diagnosis 2 colonoscopies every 5 years after 10 years from diagnosis Every 2 years or yearly after 8 years from diagnosis NS

Yes

Colonoscopy

Aliment Pharmacol Ther 2014; 39: 645-659 ª 2014 John Wiley & Sons Ltd

NS NS Every 2 years or yearly after 8–10 years from diagnosis

649

~o-Milla et al. C. Castan Table 1 | (Continued) Type of study

Design of study

Definition of UC

Follow-up since diagnosis

Screening interventions

Frequency of interventions

Cohorts Referral centre Cohorts Referral centre

Prospective Retrospective

CDC NS

Yes No

NS NS

NS NS

Prospective Retrospective

NS LJC

Yes Yes

NS Colonoscopy

Retrospective

LJC

Yes

NS

NS Every 2 years or yearly after 10 years from diagnosis NS

Prospective Prospective

LJC LJC

Yes Yes

NS NS

NS NS

Prospective

LJC

No

Colonoscopy

Author

Year

Country

Jakobsen83 Ozin84

2009 2009

Denmark Turkey

Soderlund85 Kekilli86

2009 2010

Sweden Turkey

Biancone87

2011

Italy

Katsanos88 Manninen89

2011 2011

Europe Finland

Vienne90

2011

France

Referral centre Cohorts Populationbased Cohorts

Gong91

2012

China

Cohorts

Retrospective

LJC

Yes

Colonoscopy

Hou92

2012

USA

Cohorts

Retrospective

No

NS

Jess93

2012

Denmark

Populationbased

Retrospective

Yes

NS

NS

Wei94

2012

China

Cohorts

Retrospective

Yes

Colonoscopy

NS

Beaugerie95 Campos96

2013 2013

France Brazil

Cohorts Referral centre

Prospective Prospective

ICD-9 code for UC ICD-8 or ICD-10 code for UC ICD-8 code for UC NS LJC

Every 2 years or yearly after 7–10 years from diagnosis Every 2 years or yearly after 7 years from diagnosis NS

No Yes

Colonoscopy Colonoscopy

Jess97

2013

Denmark

Retrospective

LJC

Yes

Colonoscopy

Jussila98

2013

Finland

Populationbased Cohorts

NS Every year after 10 years from diagnosis NS

Retrospective

Yes

NS

NS

Kappelman99

2013

Denmark

Populationbased

Retrospective

Yes

NS

NS

Manninen100

2013

Finland

Populationbased

Retrospective

ICD-8 or ICD-10 code for UC ICD-8 or ICD-10 code for UC ICD-9 or ICD-10 code for UC

Yes

Colonoscopy

Selinger101 Senanayake102

2013 2013

Australia Sri Lanka

Cohorts Referral centre

Retrospective Retrospective

Yes Yes

NS Colonoscopy

Every 1 year or 3 years after 8 years from diagnosis in extensive colitis and every 1 year or 3 years after 15 years from diagnosis in left-sided colitis NS Every 1 year, three or 5 years after 6–8 years from diagnosis

650

LJC LJC

Aliment Pharmacol Ther 2014; 39: 645-659 ª 2014 John Wiley & Sons Ltd

Systematic review with meta-analysis: risk of colorectal cancer in ulcerative colitis Table 1 | (Continued)

Author

Year

Country

Shivakumar103

2013

India

Type of study

Design of study

Definition of UC

Follow-up since diagnosis

Screening interventions

Frequency of interventions

Referral centre

Prospective

LJC

No

Chromocolonoscopy

Every year after 7 years from diagnosis in extensive colitis and every yearafter 10 years from diagnosis in left-sided colitis

CRC, colorectal cancer; UC, ulcerative colitis; NS, not stated; EAC, Evans and Acheson criteria;13 BC, Binder et al. criteria;14 LSC, Loftus and Silverstein criteria;15 CDC, Copenhagen diagnostic criteria;16 LJC; Lennard-Jones criteria.17

sub-group analyses and funnel plots to determine whether particular characteristics of studies were related to the sizes of the cohorts, according to the recommendations of the Cochrane Handbook for Systematic Reviews of Interventions.21 Cumulative incidence and incidence rates of CRC were combined and analysed using the generic inverse variance method, which is based on a weighted average of the effect estimates from the individual studies. The weight for each study is taken to be the inverse of the variance (one divided by the square of the standard error) of the effect estimate. A fixed-effect model was applied if the results were homogeneous; if the results were heterogeneous (I2>50%), a random-effect model was applied.22 All calculations were performed using the Review Manager program (RevMan), developed by the Cochrane Collaboration (Version 5.1. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2011).

Sub-group analysis We performed sub-analyses regardless of whether significant heterogeneity was present. Sub-analyses were performed depending on the length of follow-up, the time of evolution of the UC, the studies that only included patients with extensive colitis, the population-based studies (self-defined by the authors), the decade of study publication and the studies where the follow-up started since the diagnosis of UC. RESULTS The database search retrieved 10 033 articles, 9876 being rejected because they were not original articles. After reading the remaining 157 abstracts, we rejected 66 studies for Aliment Pharmacol Ther 2014; 39: 645-659 ª 2014 John Wiley & Sons Ltd

the reasons explained in the flow chart shown in Figure 1.23–103 Therefore, we had 91 studies evaluating the incidence of CRC in UC. Ten studies were excluded104–113 because they were updated by or overlapped with subsequent studies.50, 61, 62, 68, 71, 74, 76, 85, 88, 91, 107–109, 111–113 The remaining 81 studies met the inclusion criteria and were included in the meta-analysis (Table 1).23–103The results of the assessment of the quality of the studies using NOS scale can be found in Table S1. The 81 studies provided data from 181 923 patients (1 570 936 py), of whom 2289 had CRC; therefore, 1.26% of patients developed CRC during follow-up (Table S2).23–103 Studies were pooled using a random-effects model, which revealed the cumulative incidence of CRC in patients with UC to be 15.6/1000 patients (95% CI, 13.8–17.4). The results were heterogeneous (v2 = 717, P < 0.00001, I2 = 89%). The overall incidence rate of CRC in patients with UC was 1.58 per 1000 py (95% CI, 1.39–1.76). The results were heterogeneous (v2 = 418, P < 0.00001, I2 = 81%). The incidence rates of all studies are shown in Figure S1.

Risk of CRC in population-based studies Nineteen studies were population-based cohorts.40, 44, 46, 55, 60, 61, 63, 64, 70, 75, 76, 79, 82, 84, 88, 92, 97, 99, 100 Analysis of these studies revealed 67 141 patients with 926 755 py of follow-up and 1196 cases of CRC. The cumulative rate was 13.3/1000 patients (95% CI, 10.9– 15.6). These results were heterogeneous (v2 = 141, P < 0.00001, I2 = 87%). The incidence rate was 1.24/ 1000 py (95% CI, 1.01–1.47). The results were also heterogeneous (v2 = 86, P < 0.00001, I2 = 79%). The incidence rates of population-based studies are shown in Figure 2. 651

~o-Milla et al. C. Castan MEDLINE 3136 entries

3006 rejected

EMBASE 6666 entries

211 rejected

6640 rejected

130 full-text articles assesed for elegibility

CINAHL 212 entries

26 full-text articles assesed for elegibility

COCHRANE 19 entries

19 rejected

1 full-text articles assesed for elegibility

0 full-text articles assesed for elegibility

157 articles

7 case-controls

8 cancer registries

5 reviews

46 others studies

91 studies

10 updated

81 studies included

The other 62 studies comprised mainly cohort studies from referral centres. Analysis of these studies revealed the cumulative rate to be 17.9/1000 patients (95% CI, 15.3–20.5); the incidence rate was 1.9/1000 py (95% CI, 1.63–2.18). The results were heterogeneous (v2 = 304– 535, P < 0.00001, I2 = 80–89%).

Risk of CRC based on duration of UC Nineteen studies stratified results into intervals of 10 years of disease duration.24, 27, 30, 32, 35, 36, 38– 40, 42, 45, 46, 50, 57, 58, 71, 75, 77, 78 In the first decade after the diagnosis of UC, the incidence rate was 0.91/ 1000 py (95% CI, 0.61–1.2) and the results were homogeneous (v2 = 15, P = 0.47, I2 = 0%). The incidence rate was 4.07/1000 py (95% CI, 2.58–5.56) in the second decade and 4.55/1000 py (95% CI, 2.64–6.46) in 652

Figure 1 | Flow chart of literature search for studies describing cumulative incidence and incidence rate of colorectal cancer in ulcerative colitis patients.

the third decade. The results were heterogeneous in the second and third decades (v2 = 80–111, P < 0.00001, I2 = 73–85%).

Risk of CRC depending on the extension of the disease Eight of the 81 studies included only patients with extensive colitis.23, 36, 49, 50, 52, 55, 66, 78 Analysis of these 1785 patients revealed the cumulative incidence of CRC in those with extensive colitis to be 44.4/1000 patients (95% CI, 22.8–66). The results were heterogeneous (v2 = 48, P < 0.00001, I2 = 86%). The incidence rate was higher than the overall incidence rate: 4.02/1000 py (95% CI, 2.74–5.31). These results were moderately heterogeneous (v2 = 13, P = 0.07, I2 = 47%). Aliment Pharmacol Ther 2014; 39: 645-659 ª 2014 John Wiley & Sons Ltd

Systematic review with meta-analysis: risk of colorectal cancer in ulcerative colitis Incidence rate Study Hendriksen Gilat. Rutegard Mellemkjaer Karlen Palli Askling Bernstein Winther Jess Lakatos Jess. Soderlund Jakobsen Manninen Jess Kappelman Jess Manninen

Year 1985 1988 1989 1995 1999 2000 2001 2001 2004 2006 2006 2007 2009 2009 2011 2012 2013 2013 2013

Incidence rate SE Weight 0.504 3.3% 1.3343499 2.18432328 0.42791292 4.0% 1.69725 2.9440628 0.4% 1.28357935 0.19793344 7.0% 6.7% 1.178133 0.21497008 4.3% 1.26951885 0.4012022 7.9% 1.32904941 0.13086808 4.8% 2.49173659 0.35551861 7.5% 0.58322118 0.16170927 3.9% 1.07777977 0.43976457 4.1% 1.51798225 0.42069286 7.5% 0.59854639 0.15992037 8.0% 1.36363636 0.11728308 0.999001 0.70604744 2.1% 1.19850187 0.4234804 4.1% 2.4% 1.050086 0.6411 8.4% 1.593814 0.0761817 7.3% 0.6642458 0.1714505 1.023345 0.2557053 6.2%

IV, Random, 95% CI 1.33 [0.35, 2.32] 2.18 [1.35, 3.02] 2.94 [–0.38, 6.27] 1.28 [0.90, 1.67] 1.18 [0.76, 1.60] 1.27 [0.48, 2.06] 1.33 [1.07, 1.59] 2.49 [1.79, 3.19] 0.58 [0.27, 0.90] 1.08 [0.22, 1.94] 1.52 [0.69, 2.34] 0.60 [0.29, 0.91] 1.36 [1.13, 1.59] 1.00 [–0.38, 2.38] 1.20 [0.37, 2.03] 1.05 [–0.21, 2.31] 1.59 [1.44, 1.74] 0.66 [0.33, 1.00] 1.02 [0.52, 1.52]

1.24 [1.01, 1.47] 100.0% Total (95% CI) Heterogeneity: Tau2 = 0.16; Chi2 = 86.36, df = 18 (P < 0.00001); I2 = 79% Test for overall effect: Z = 10.59 (P < 0.00001)

Incidence rate IV, Random, 95% CI

–10 –5

0

5

10

Figure 2 | Incidence rates of population-based studies reporting colorectal cancer in patients with ulcerative colitis (per 1000 patient-years).

Incidence of CRC reported by surveillance programme studies Eighteen studies reported the results of surveillance programmes49–55, 57, 68, 70, 73, 74, 78, 82, 86, 100, 103 and included 4302 patients with 52 593 py of follow-up and 145 cases of CRC. The cumulative incidence of the studies based on surveillance programmes was 30.1/1000 patients (95% CI, 20–40.2); the incidence rate was 2.6/ 1000 py (95% CI, 1.74–3.46). Both were higher than the overall pooled rates (15.6/1000 patients and 1.58/1000 py). The results were heterogeneous (v2 = 63–65, P < 0.00001, I2 = 75–76%). In 34 studies, CRC surveillance started since the diagnosis of UC.34, 38, 41, 42, 44–46, 49, 50, 58–60, 63, 64, 66– 68, 70, 71, 74–76, 78, 80, 82, 83, 85–89, 91, 93, 94, 96–102 The cumulative incidence and the incidence rates were 14.5/1000 patients (95% CI, 12.3–16.8) and 1.35/1000 py (95% CI, 1.13–1.57) respectively. The results were heterogeneous (v2 = 28–263, P < 0.00001, I2 = 85–88%). Evolution of the risk of CRC depending on the year of publication We analysed the results classifying the studies by decade of publication. The cumulative incidence and the incidence rates decreased from 33.1/1000 patients and 4.29/ 1000 py, respectively, in studies published in the 1950s Aliment Pharmacol Ther 2014; 39: 645-659 ª 2014 John Wiley & Sons Ltd

to 9.1/1000 patients and 1.21/1000 py in those published in the last decade (Table 2). The results were heterogeneous (v2 = 4–183, P = 0.00001–0.05, I2 = 53–92%).

DISCUSSION In the present study, that included all articles reporting incidence of CRC in UC patients (independently of their design), we have found that the overall risk of CRC in 181 923 UC patients was 1.69 per 1000 py, 0.91/1000 py in the first decade after the diagnosis of UC, 4.07/1000 py in the second and 4.55/1000 py in the third decade. These updated figures are lower than those reported by Eaden et al. in their 2001 meta-analysis, 3/1000 py overall, and 2%, 8% and 18% for each decade after diagnosis.2 These rates are considerably higher than the incidence of CRC reported in the general population.2 The incidence of colorectal cancer in general population ranges from 0.4/1000 py in Australia, New Zealand, USA and Western Europe to 0.1/1000 py in Africa.114 We would like to emphasise that, in our systematic review, 72% of the total of the studies (58 of 81 studies) and 87% of the studies published after 1990 (46 of 53 studies) reported an incidence rate lower than 3/1000 py, the overall incidence rate that Eaden et al. reported in their meta-analysis.2 However, studies performed after the publication of that meta-analysis have reported lower 653

~o-Milla et al. C. Castan Table 2 | Risk of developing colorectal cancer (CRC) in ulcerative colitis stratified by decade of publication of studies

Decade

Number of studies

Patientyears

Number of cases of CRC

Cumulative incidence per 1000 py (95% CI)

Incidence rate per 1000 py (95% CI)

1950s 1960s 1970s 1980s 1990s 2000s 2010–2013

3 7 4 14 12 23 18

4759 19 304 12 909 123 866 87 499 369 829 861 478

22 80 40 310 132 525 1180

33.15 31.43 29.47 31.37 15.59 14.26 9.05

4.29 4.18 3.22 2.58 1.53 1.29 1.21

(0.58–65.73) (20.21–42.65) (2.47–56.37) (20.36–42.38) (9.6–21.57) (10.47–18.05) (6.8–11.3)

(0.95–7.64) (2.67–5.68) (0.67–5.77) (1.81–3.34) (1.06–2) (1–1.58) (0.95–1.48)

py, patient-years; CI, confidence interval.

incidence rates of CRC in UC patients.70, 75, 76 It is important to note the striking downward trend in the incidence rate over the last few decades80, 85: the incidence rates decreased from 4.29/1000 py in studies published in the 1950s to 1.21/1000 py in studies published in the last decade. Several hypotheses may be put forward to explain this trend, such as the adherence to endoscopic surveillance programmes, higher rates of colectomy in patients with dysplasia or a more aggressive control of the inflammatory activity. In this respect, 5-aminosalicylates have been suggested to have a chemoprophylactic impact on CRC associated with UC;115, 116 although some studies have failed to prove their preventive effect, others have shown that these agents seem to interrupt the progression from healthy mucosa to dysplasia and carcinoma.117–120 Recent studies have reported that thiopurines would reduce the risk of CRC in UC patients, also by controlling the inflammation.121–123 Although data on the impact of anti-TNF agents in the development of CRC are still lacking, it is conceivable that an optimal control of mucosal inflammation could decrease this risk. In the present study, several sub-analyses have been performed to identify patients with a higher risk of developing CRC that could be taken into account for surveillance programmes. To this respect, in agreement with previous data, the risk of CRC in UC patients was increased with larger extensions of the disease. We also observed that this risk was increased with longer durations of the UC, although it was much lower than that previously reported.2 Thus, incidence rates of CRC at 10, 20 and 30 years after diagnosis of UC in our study and in Eaden’s study were 0.91 vs. 2, 4.07 vs. 7 and 4.55 vs. 12, all measured in cases per 1000 py. Based on the results from Eaden’s study, considering that the risk of CRC increases with the time of evolution 654

of the UC, several guidelines have established that the first screening colonoscopy should be offered 8 to 10 years after the diagnosis in patients with extensive colitis, and 15 years after the onset of symptoms in patients with left-sided colitis.9–11 After that, surveillance colonoscopies should be repeated every 1–2 years. New ECCO guidelines published in 2013 recommend a screening colonoscopy 8 years after the onset of colitic symptoms.124 Ongoing surveillance should be repeated every 1, 3 or 5 years depending on the risk factors. Nevertheless, a Cochrane meta-analysis did not find clear evidence that endoscopic surveillance prolonged survival in patients with extensive colitis, although it showed that CRCs tend to be detected at an earlier stage. New endoscopic techniques, such as chromoscopy, have been shown to be much more efficient for the detection of dysplasia than the performance of random biopsies;125 their incorporation into endoscopic surveillance might optimise the screening time points. Regarding the risk of CRC in paediatric UC population, although studies are scarce, they have also reported higher incidence rates than the overall rate for adults with UC,62, 63, 70 thus supporting previous findings,13, 14 namely, that early onset of UC7, 8 could confer a higher risk of developing CRC.28, 29, 83 Considering only population-based studies – that is, excluding studies from referral centres – the incidence rate of CRC is even lower.71, 76, 77 Our sub-analysis of population-based studies revealed that the incidence rate was 1.24 per 1000 py vs. 1.9 per 1000 py for studies with different designs (tertiary or referral hospital-based cohorts, private clinic series, and surgical series). Of note, only 5 of the 19 population-based studies had been included in the meta-analysis by Eaden et al.,41, 45, 47, 56, 61 as the other 14 were published after 2000.62, 65, 71, 76, 77, 80, 83, 85, 89, 93, 97, 99, 100 Aliment Pharmacol Ther 2014; 39: 645-659 ª 2014 John Wiley & Sons Ltd

Systematic review with meta-analysis: risk of colorectal cancer in ulcerative colitis To have an overview of the complete history of the development of CRC in UC patients, a sub-analysis of the studies in which the surveillance had started at the diagnosis of the disease was performed, finding that the incidence rate was even lower than the overall incidence rate, and closer to the general population without UC. Our analysis is subject to a series of limitations. Our analysis covers a large number of studies in which high heterogeneity of design, size, length of follow-up and results exists, leading to pooled statistical heterogeneity. We have to assume that, even trying to reduce heterogeneity, this could not be alleviated even performing sub-analyses. The analysis is also limited by the small sample size of some cohorts, extracted from studies carried out by surgical teams or studies based on surveillance programmes in referral centres with active follow-up. These limitations could lead to higher incidence rates of CRC in small cohorts. Consequently, our results may be overestimated due to the inclusion of a considerable number of studies performed in referral centres (vs. population-based studies), mainly when a rare event like CRC is evaluated. Another limitation of our paper may be the differential incidences according to the geographical area. This may partially explain the significant heterogeneity of the results.126 However, we believe that despite the limitations described, our results are sufficiently robust to be considered valid and provide valuable updated information about the current risk of CRC in UC. In conclusion, our meta-analysis estimates an overall incidence rate of CRC of only 1.58 per 1000 py in UC patients; this incidence rate is considerably lower than previously estimated. As described in precedent literature, the extension and the duration of the disease increase the risk of CRC in this population. On the other

hand, the incidence of CRC in UC patients seems to have decreased during the last few decades, and this might be explained by a tighter control of the inflammation, higher colectomy rates, the use of drugs with chemopreventive effects and a better adherence to endoscopic surveillance programmes in high-risk patients. All these factors should be taken into account when critically reviewing current CRC surveillance programmes in UC patients.

AUTHORSHIP Guarantor of the article: C. Casta~ no-Milla. Author contributions: J.P.G. and M.C. initiated and designed the study. C.C. and M.C. performed the literature search. C.C. and J.P.G. performed the statistical analyses and produced the tables and figures. C.C. wrote the first manuscript draft and all the authors critically revised the manuscript. All authors approved the final version of the manuscript. ACKNOWLEDGEMENTS Declaration of personal and funding interests: None. SUPPORTING INFORMATION Additional Supporting Information may be found in the online version of this article: Figure S1. Incidence rates of colorectal cancer in patients with ulcerative colitis (per 1000 patient-years). Table S1. Results of the assessment of the quality of the studies using NOS scale. Table S2. Patient characteristics. Appendix S1. PRISMA checklist. Appendix S2. Newcastle-Ottawa quality assessment scale for cohort studies.

REFERENCES 1. Ullman TA, Itzkowitz SH. Intestinal inflammation and cancer. Gastroenterology 2011; 140: 1807–16. 2. Eaden JA, Abrams KR, Mayberry JF. The risk of colorectal cancer in ulcerative colitis: a meta-analysis. Gut 2001; 48: 526–35. 3. Brentnall TA, Haggitt RC, Rabinovitch PS, et al. Risk and natural history of colonic neoplasia in patients with primary sclerosing cholangitis and ulcerative colitis. Gastroenterology 1996; 110: 331–8. Aliment Pharmacol Ther 2014; 39: 645-659 ª 2014 John Wiley & Sons Ltd

4. Broome U, Lindberg G, Lofberg R. Primary sclerosing cholangitis in ulcerative colitis–a risk factor for the development of dysplasia and DNA aneuploidy? Gastroenterology 1992; 102: 1877–80. 5. D’Haens GR, Lashner BA, Hanauer SB. Pericholangitis and sclerosing cholangitis are risk factors for dysplasia and cancer in ulcerative colitis. Am J Gastroenterol 1993; 88: 1174–8. 6. Nuako KW, Ahlquist DA, Mahoney DW, Schaid DJ, Siems DM, Lindor

NM. Familial predisposition for colorectal cancer in chronic ulcerative colitis: a case-control study. Gastroenterology 1998; 115: 1079–83. 7. Devroede GJ, Taylor WF, Sauer WG, Jackman RJ, Stickler GB. Cancer risk and life expectancy of children with ulcerative colitis. N Engl J Med 1971; 285: 17–21. 8. Ekbom A, Helmick C, Zack M, Adami HO. Increased risk of largebowel cancer in Crohn’s disease with colonic involvement. Lancet 1990; 336: 357–9. 655

~o-Milla et al. C. Castan 9. Cairns SR, Scholefield JH, Steele RJ, et al. Guidelines for colorectal cancer screening and surveillance in moderate and high risk groups (update from 2002). Gut 2010; 59: 666–89. 10. Biancone L, Michetti P, Travis S, et al. European evidence-based Consensus on the management of ulcerative colitis: special situations. J Crohns Colitis 2008; 2: 63–92. 11. Farraye FA, Odze RD, Eaden J, et al. AGA medical position statement on the diagnosis and management of colorectal neoplasia in inflammatory bowel disease. Gastroenterology 2010; 138: 738–45. 12. Liberati A, Altman DG, Tetzlaff J, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. J Clin Epidemiol 2009; 62: e1–34. 13. Evans JG, Acheson ED. An epidemiological study of ulcerative colitis and regional enteritis in the Oxford area. Gut 1965; 6: 311–24. 14. Binder V, Both H, Hansen PK, Hendriksen C, Kreiner S, TorpPedersen K. Incidence and prevalence of ulcerative colitis and Crohn’s disease in the County of Copenhagen, 1962 to 1978. Gastroenterology 1982; 83: 563–8. 15. Loftus EV Jr, Silverstein MD, Sandborn WJ, Tremaine WJ, Harmsen WS, Zinsmeister AR. Crohn’s disease in Olmsted County, Minnesota, 1940-1993: incidence, prevalence, and survival. Gastroenterology 1998; 114: 1161–8. 16. Langholz E. Ulcerative colitis. An epidemiological study based on a regional inception cohort, with special reference to disease course and prognosis. Dan Med Bull 1999; 46: 400–15. 17. Lennard-Jones JE. Classification of inflammatory bowel disease. Scand J Gastroenterol Suppl 1989; 170: 2–6. 18. Stang A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in metaanalyses. Eur J Epidemiol 2010; 25: 603–5. 19. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med 2002; 21: 1539–58. 20. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ 2003; 327: 557–60. 21. Higgins JPT, Green S, Cochrane Collaboration. Cochrane Handbook 656

22.

23.

24.

25.

26.

27.

28.

29.

30.

31.

32.

33.

34.

35.

36.

37.

for Systematic Reviews of Interventions. Chichester, England; Hoboken, NJ: Wiley-Blackwell, 2008. DerSimonian R, Laird N. Metaanalysis in clinical trials. Control Clin Trials 1986; 7: 177–88. Flood CA, Hiatt RB, Karush A, Lepore MJ. Prognosis in chronic ulcerative colitis. J Chronic Dis 1956; 4: 267–82. Thorlakson RH. Carcinoma of the colon and rectum associated with chronic ulcerative colitis. Surg Gynecol Obstet 1956; 103: 41–50. Banks BM, Korelitz BI, Zetzel L. The course of nonspecific ulcerative colitis: review of twenty years’ experience and late results. Gastroenterology 1957; 32: 983–1012. Dennis C. Cancer risk in ulcerative colitis: formidability per patient-year of late disease. Surgery 1961; 50: 568–71. Russell IS, Hughes ES. Carcinoma of the colon complicating ulcerative colitis. Aust N Z J Surg 1961; 30: 306–11. Hijmans JC, Enzer NB. Ulcerative colitis in childhood. A study of 43 cases. Pediatrics 1962; 29: 389–403. Korelitz BI, Gribetz D. The prognosis of ulcerative colitis with onset in childhood. II. The steroid era. Ann Intern Med 1962; 57: 592–7. Edwards FC, Truelove SC. The course and prognosis of ulcerative colitis. III. Complications. Gut 1964; 5: 1–22. Macdougall IP. The cancer risk in ulcerative colitis. Lancet 1964; 2: 655–8. De Dombal FT, Watts JM, Watkinson G, Goligher JC. Local complications of ulcerative colitis: stricture, pseudopolyposis, and carcinoma of colon and rectum. Br Med J 1966; 1: 1442–7. Aktan H, Paykoc Z, Ertan A. Ulcerative colitis in Turkey: clinical review of sixty cases. Dis Colon Rectum 1970; 13: 62–5. Gilat T, Zemishlany Z, Ribak J, Bennaroya Y, Lilos P. Ulcerative colitis in the Jewish population of Tel-Aviv Uafo. II: the rarity of malignant degeneration. Gastroenterology 1974; 67: 933–8. Baker WN, Glass RE, Ritchie JK, Aylett SO. Cancer of the rectum following colectomy and ileorectal anastomosis for ulcerative colitis. Br J Surg 1978; 65: 862–8. Kewenter J, Ahlman H, Hulten L. Cancer risk in extensive ulcerative colitis. Ann Surg 1978; 188: 824–8. Lanfranchi GA, Brignola C, Michelini M, et al. Clinical course of ulcerative colitis in Italy. Digestion 1980; 20: 106–10.

38. Prior P, Gyde SN, Macartney JC, Thompson H, Waterhouse JA, Allan RN. Cancer morbidity in ulcerative colitis. Gut 1982; 23: 490–7. 39. Johnson WR, McDermott FT, Hughes ES, Pihl EA, Milne BJ, Price AB. Carcinoma of the colon and rectum in inflammatory disease of the intestine. Surg Gynecol Obstet 1983; 156: 193–7. 40. Katzka I, Brody B. Cancer risk in ulcerative colitis. Gastroenterology 1983; 85: 787–8. 41. Hendriksen C, Kreiner S, Binder V. Long term prognosis in ulcerative colitis–based on results from a regional patient group from the county of Copenhagen. Gut 1985; 26: 158–63. 42. Maratka Z, Nedbal J, Kocianova J, Havelka J, Kudrmann J, Hendl J. Incidence of colorectal cancer in proctocolitis: a retrospective study of 959 cases over 40 years. Gut 1985; 26: 43–9. 43. Mir-Madjlessi SH, Forouzandeh B, Ghadimi R. Ulcerative colitis in Iran: a review of 112 cases. Am J Gastroenterol 1985; 80: 862–6. 44. Mir-Madjlessi SH, Farmer RG, Easley KA, Beck GJ. Colorectal and extracolonic malignancy in ulcerative colitis. Cancer 1986; 58: 1569–74. 45. Gilat T, Fireman Z, Grossman A, et al. Colorectal cancer in patients with ulcerative colitis. A population study in central Israel. Gastroenterology 1988; 94: 870–7. 46. Gyde SN, Prior P, Allan RN, et al. Colorectal cancer in ulcerative colitis: a cohort study of primary referrals from three centres. Gut 1988; 29: 206–17. 47. Rutegard JN, Ahsgren LR, Janunger KG. Ulcerative colitis. Colorectal cancer risk in an unselected population. Ann Surg 1988; 208: 721–4. 48. Kvist N, Jacobsen O, Kvist HK, et al. Malignancy in ulcerative colitis. Scand J Gastroenterol 1989; 24: 497–506. 49. Lashner BA, Silverstein MD, Hanauer SB. Hazard rates for dysplasia and cancer in ulcerative colitis. Results from a surveillance program. Dig Dis Sci 1989; 34: 1536–41. 50. Lennard-Jones JE, Melville DM, Morson BC, Ritchie JK, Williams CB. Precancer and cancer in extensive ulcerative colitis: findings among 401 patients over 22 years. Gut 1990; 31: 800–6. 51. Lofberg R, Brostrom O, Karlen P, Tribukait B, Ost A. Colonoscopic surveillance in long-standing total ulcerative colitis–a 15-year follow-up Aliment Pharmacol Ther 2014; 39: 645-659 ª 2014 John Wiley & Sons Ltd

Systematic review with meta-analysis: risk of colorectal cancer in ulcerative colitis

52.

53.

54.

55.

56.

57.

58.

59.

60.

61.

62.

63.

study. Gastroenterology 1990; 99: 1021–31. Lynch DA, Lobo AJ, Sobala GM, Dixon MF, Axon AT. Failure of colonoscopic surveillance in ulcerative colitis. Gut 1993; 34: 1075–80. Connell WR, Lennard-Jones JE, Williams CB, Talbot IC, Price AB, Wilkinson KH. Factors affecting the outcome of endoscopic surveillance for cancer in ulcerative colitis. Gastroenterology 1994; 107: 934–44. Jonsson B, Ahsgren L, Andersson LO, Stenling R, Rutegard J. Colorectal cancer surveillance in patients with ulcerative colitis. Br J Surg 1994; 81: 689–91. Lashner BA, Provencher KS, Bozdech JM, Brzezinski A. Worsening risk for the development of dysplasia or cancer in patients with chronic ulcerative colitis. Am J Gastroenterol 1995; 90: 377–80. Mellemkjaer L, Olsen JH, Frisch M, Johansen C, Gridley G, McLaughlin JK. Cancer in patients with ulcerative colitis. Int J Cancer 1995; 60: 330–3. Rozen P, Baratz M, Fefer F, Gilat T. Low incidence of significant dysplasia in a successful endoscopic surveillance program of patients with ulcerative colitis. Gastroenterology 1995; 108: 1361–70. Stewenius J, Adnerhill I, Anderson H, et al. Incidence of colorectal cancer and all cause mortality in nonselected patients with ulcerative colitis and indeterminate colitis in Malmo, Sweden. Int J Colorectal Dis 1995; 10: 117–22. Radhakrishnan S, Zubaidi G, Daniel M, Sachdev GK, Mohan AN. Ulcerative colitis in Oman. A prospective study of the incidence and disease pattern from 1987 to 1994. Digestion 1997; 58: 266–70. Triantafillidis JK, Emmanouilidis A, Manousos ON, et al. Ulcerative colitis in Greece: clinicoepidemiological data, course, and prognostic factors in 413 consecutive patients. J Clin Gastroenterol 1998; 27: 204–10. Karlen P, Lofberg R, Brostrom O, Leijonmarck CE, Hellers G, Persson PG. Increased risk of cancer in ulcerative colitis: a population-based cohort study. Am J Gastroenterol 1999; 94: 1047–52. Palli D, Trallori G, Bagnoli S, et al. Hodgkin’s disease risk is increased in patients with ulcerative colitis. Gastroenterology 2000; 119: 647–53. Wandall EP, Damkier P, Moller Pedersen F, Wilson B, Schaffalitzky de Muckadell OB. Survival and incidence of colorectal cancer in patients with ulcerative colitis in

Aliment Pharmacol Ther 2014; 39: 645-659 ª 2014 John Wiley & Sons Ltd

64.

65.

66.

67.

68.

69.

70.

71.

72.

73.

74.

Funen county diagnosed between 1973 and 1993. Scand J Gastroenterol 2000; 35: 312–7. Askling J, Dickman PW, Karlen P, et al. Family history as a risk factor for colorectal cancer in inflammatory bowel disease. Gastroenterology 2001; 120: 1356–62. Bernstein CN, Blanchard JF, Kliewer E, Wajda A. Cancer risk in patients with inflammatory bowel disease: a population-based study. Cancer 2001; 91: 854–62. Lindberg BU, Broome U, Persson B. Proximal colorectal dysplasia or cancer in ulcerative colitis. The impact of primary sclerosing cholangitis and sulfasalazine: results from a 20-year surveillance study. Dis Colon Rectum 2001; 44: 77–85. Viscido A, Bagnardi V, Sturniolo GC, et al. Survival and causes of death in Italian patients with ulcerative colitis. A GISC nationwide study. Dig Liver Dis 2001; 33: 686–92. Biasco G, Rossini FP, Hakim R, et al. Cancer surveillance in ulcerative colitis: critical analysis of long-term prospective programme. Dig Liver Dis 2002; 34: 339–42. Al-Shamali MA, Kalaoui M, Patty I, Hasan F, Khajah A, Al-Nakib B. Ulcerative colitis in Kuwait: a review of 90 cases. Digestion 2003; 67: 218–24. Hata K, Watanabe T, Kazama S, et al. Earlier surveillance colonoscopy programme improves survival in patients with ulcerative colitis associated colorectal cancer: results of a 23-year surveillance programme in the Japanese population. Br J Cancer 2003; 89: 1232–6. Winther KV, Jess T, Langholz E, Munkholm P, Binder V. Long-term risk of cancer in ulcerative colitis: a population-based cohort study from Copenhagen County. Clin Gastroenterol Hepatol 2004; 2: 1088– 95. Katsanos KH, Christodoulou DK, Michael M, et al. Inflammatory bowel disease-related dysplasia and cancer: a referral center study in northwestern Greece. Eur J Intern Med 2005; 16: 170–5. Khorrami Mashhadi S, Trapero M, Gisbert JP, Gomez Dominguez E, Mate Jimenez J. A pilot study on the endoscopic surveillance of colorectal dysplasia and cancer in long-standing ulcerative colitis. Rev Esp Enferm Dig 2005; 97: 16–23. Lindberg J, Stenling R, Palmqvist R, Rutegard J. Efficiency of colorectal cancer surveillance in patients with ulcerative colitis: 26 years’ experience in a patient cohort from a defined

75.

76.

77.

78.

79.

80.

81.

82.

83.

84.

85.

population area. Scand J Gastroenterol 2005; 40: 1076–80. Venkataraman S, Mohan V, Ramakrishna BS, et al. Risk of colorectal cancer in ulcerative colitis in India. J Gastroenterol Hepatol 2005; 20: 705–9. Jess T, Loftus EV Jr, Velayos FS, et al. Risk of intestinal cancer in inflammatory bowel disease: a population-based study from olmsted county, Minnesota. Gastroenterology 2006; 130: 1039–46. Lakatos L, Mester G, Erdelyi Z, et al. Risk factors for ulcerative colitisassociated colorectal cancer in a Hungarian cohort of patients with ulcerative colitis: results of a population-based study. Inflamm Bowel Dis 2006; 12: 205–11. Rutter MD, Saunders BP, Wilkinson KH, et al. Thirty-year analysis of a colonoscopic surveillance program for neoplasia in ulcerative colitis. Gastroenterology 2006; 130: 1030–8. Ghazzawi I, Al-Mrayat Z. Review of chronic ulcerative colitis cases at King Hussein Medical Centre, Jordan. East Mediterr Health J 2007; 13: 294–300. Jess T, Riis L, Vind I, et al. Changes in clinical characteristics, course, and prognosis of inflammatory bowel disease during the last 5 decades: a population-based study from Copenhagen, Denmark. Inflamm Bowel Dis 2007; 13: 481–9. Goldacre MJ, Wotton CJ, Yeates D, Seagroatt V, Jewell D. Cancer in patients with ulcerative colitis, Crohn’s disease and coeliac disease: record linkage study. Eur J Gastroenterol Hepatol 2008; 20: 297–304. Chow DK, Leong RW, Tsoi KK, et al. Long-term follow-up of ulcerative colitis in the Chinese population. Am J Gastroenterol 2009; 104: 647–54. Jakobsen C, Paerregaard A, Munkholm P, Wewer V. Paediatric inflammatory bowel disease during a 44-year period in Copenhagen County: occurrence, course and prognosis–a population-based study from the Danish Crohn Colitis Database. Eur J Gastroenterol Hepatol 2009; 21: 1291–301. Ozin Y, Kilic MZ, Nadir I, et al. Clinical features of ulcerative colitis and Crohn’s disease in Turkey. J Gastrointestin Liver Dis 2009; 18: 157–62. Soderlund S, Brandt L, Lapidus A, et al. Decreasing time-trends of colorectal cancer in a large cohort of patients with inflammatory bowel disease. Gastroenterology 2009; 136: 1561–7. 657

~o-Milla et al. C. Castan 86. Kekilli M, Dagli U, Kalkan IH, et al. Low incidence of colorectal dysplasia and cancer among patients with ulcerative colitis: a Turkish referral centre study. Scand J Gastroenterol 2010; 45: 434–9. 87. Biancone L, Zuzzi S, Ranieri M, et al. Fistulizing pattern in Crohn’s disease and pancolitis in ulcerative colitis are independent risk factors for cancer: a single-center cohort study. J Crohns Colitis 2012; 6: 578–87. 88. Katsanos KH, Tatsioni A, Pedersen N, et al. Cancer in inflammatory bowel disease 15 years after diagnosis in a population-based European Collaborative follow-up study. J Crohns Colitis 2011; 5: 430– 42. 89. Manninen P, Karvonen AL, Huhtala H, et al. Mortality in ulcerative colitis and Crohn’s disease. A populationbased study in Finland. J Crohns Colitis 2012; 6: 524–8. 90. Vienne A, Simon T, Cosnes J, et al. Low prevalence of colonoscopic surveillance of inflammatory bowel disease patients with longstanding extensive colitis: a clinical practice survey nested in the CESAME cohort. Aliment Pharmacol Ther 2011; 34: 188–95. 91. Gong W, Lv N, Wang B, et al. Risk of ulcerative colitis-associated colorectal cancer in China: a multicenter retrospective study. Dig Dis Sci 2012; 57: 503–7. 92. Hou JK, Kramer JR, Richardson P, Mei M, El-Serag HB. Risk of colorectal cancer among Caucasian and African American veterans with ulcerative colitis. Inflamm Bowel Dis 2012; 18: 1011–7. 93. Jess T, Simonsen J, Jorgensen KT, Pedersen BV, Nielsen NM, Frisch M. Decreasing risk of colorectal cancer in patients with inflammatory bowel disease over 30 years. Gastroenterology 2012; 143: 375–81. 94. Wei SC, Shieh MJ, Chang MC, Chang YT, Wang CY, Wong JM. Long-term follow-up of ulcerative colitis in Taiwan. J Chin Med Assoc 2012; 75: 151–5. 95. Beaugerie L, Svrcek M, Seksik P, et al. Risk of colorectal high-grade dysplasia and cancer in a prospective observational cohort of patients with inflammatory bowel disease. Gastroenterology 2013; 145: 166–175. e168 96. Campos FG, Teixeira MG, Scanavini A, de Almeida MG, Nahas SC, Cecconello I. Intestinal and extraintestinal neoplasia in patients with inflammatory bowel disease in a 658

97.

98.

99.

100.

101.

102.

103.

104.

105.

106.

107.

tertiary care hospital. Arq Gastroenterol 2013; 50: 123–9. Jess T, Horvath-Puho E, Fallingborg J, Rasmussen HH, Jacobsen BA. Cancer risk in inflammatory bowel disease according to patient phenotype and treatment: a Danish Population-Based Cohort Study. Am J Gastroenterol 2013; 108: 1869–76. Jussila A, Virta LJ, Pukkala E, Farkkila MA. Malignancies in patients with inflammatory bowel disease: a nationwide register study in Finland. Scand J Gastroenterol 2013; 48: 1405–13. Kappelman MD, Farkas DK, Long MD, et al. Risk of cancer in patients with inflammatory bowel diseases: a Nationwide Population-based Cohort Study with 30 years of follow-up evaluation. Clin Gastroenterol Hepatol 2013; 12: 265–73. Manninen P, Karvonen AL, Huhtala H, et al. The risk of colorectal cancer in patients with inflammatory bowel diseases in Finland: a follow-up of 20 years. J Crohns Colitis 2013; 7: e551–7. Selinger CP, Andrews JM, Titman A, et al. Long-term follow-up reveals low incidence of colorectal cancer, but frequent need for resection, among Australian patients with inflammatory bowel disease. Clin Gastroenterol Hepatol 2013; doi: 10. 1016/j.cgh.2013.05.017 [Epub ahead of print]. Senanayake SM, Fernandopulle AN, Niriella MA, et al. The long-term outcomes of a cohort of Sri Lankan patients with ulcerative colitis: a retrospective study at two national referral centers and review of literature. Clin Exp Gastroenterol 2013; 6: 195–200. Shivakumar BM, Lakshmankumar B, Rao L, Bhat G, Suvarna D, Pai CG. Colorectal neoplasia in long-standing ulcerative colitis – a prospective study from a low-prevalence area. Colorectal Dis 2013; 15: e462–8. Ekbom A, Helmick C, Zack M, Adami HO. Ulcerative colitis and colorectal cancer. A population-based study. N Engl J Med 1990; 323: 1228–33. Langholz E, Munkholm P, Davidsen M, Binder V. Colorectal cancer risk and mortality in patients with ulcerative colitis. Gastroenterology 1992; 103: 1444–51. Stonnington CM, Phillips SF, Melton LJ 3rd, Zinsmeister AR. Chronic ulcerative colitis: incidence and prevalence in a community. Gut 1987; 28: 402–9. Winther KV, Jess T, Langholz E, Munkholm P, Binder V. Survival

108.

109.

110.

111.

112.

113.

114.

115.

116.

117.

118.

and cause-specific mortality in ulcerative colitis: follow-up of a population-based cohort in Copenhagen County. Gastroenterology 2003; 125: 1576–82. Katsanos KH, Vermeire S, Christodoulou DK, et al. Dysplasia and cancer in inflammatory bowel disease 10 years after diagnosis: results of a population-based European collaborative follow-up study. Digestion 2007; 75: 113–21. Lindberg J, Stenling R, Palmqvist R, Rutegard J. Early onset of ulcerative colitis: long-term follow-up with special reference to colorectal cancer and primary sclerosing cholangitis. J Pediatr Gastroenterol Nutr 2008; 46: 534–8. Lennard-Jones JE, Morson BC, Ritchie JK, Williams CB. Cancer surveillance in ulcerative colitis. Experience over 15 years. Lancet 1983; 2: 149–52. Brostrom O, Lofberg R, Nordenvall B, Ost A, Hellers G. The risk of colorectal cancer in ulcerative colitis. An epidemiologic study. Scand J Gastroenterol 1987; 22: 1193–9. Biasco G, Brandi G, Paganelli GM, et al. Colorectal cancer in patients with ulcerative colitis. A prospective cohort study in Italy. Cancer 1995; 75: 2045–50. Palli D, Trallori G, Saieva C, et al. General and cancer specific mortality of a population based cohort of patients with inflammatory bowel disease: the Florence Study. Gut 1998; 42: 175–9. Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 2010; 127: 2893–917. Bernstein CN, Nugent Z, Blanchard JF. 5-aminosalicylate is not chemoprophylactic for colorectal cancer in IBD: a population based study. Am J Gastroenterol 2011; 106: 731–6. Terdiman JP, Steinbuch M, Blumentals WA, Ullman TA, Rubin DT. 5-Aminosalicylic acid therapy and the risk of colorectal cancer among patients with inflammatory bowel disease. Inflamm Bowel Dis 2007; 13: 367–71. Velayos FS, Terdiman JP, Walsh JM. Effect of 5-aminosalicylate use on colorectal cancer and dysplasia risk: a systematic review and metaanalysis of observational studies. Am J Gastroenterol 2005; 100: 1345–53. Ullman T, Croog V, Harpaz N, et al. Progression to colorectal neoplasia in

Aliment Pharmacol Ther 2014; 39: 645-659 ª 2014 John Wiley & Sons Ltd

Systematic review with meta-analysis: risk of colorectal cancer in ulcerative colitis ulcerative colitis: effect of mesalamine. Clin Gastroenterol Hepatol 2008; 6: 1225–30. 119. Rubin DT, LoSavio A, Yadron N, Huo D, Hanauer SB. Aminosalicylate therapy in the prevention of dysplasia and colorectal cancer in ulcerative colitis. Clin Gastroenterol Hepatol 2006; 4: 1346–50. 120. Matula S, Croog V, Itzkowitz S, et al. Chemoprevention of colorectal neoplasia in ulcerative colitis: the effect of 6-mercaptopurine. Clin Gastroenterol Hepatol 2005; 3: 1015–21. 121. van Schaik FD, van Oijen MG, Smeets HM, van der Heijden GJ, Siersema PD, Oldenburg B. Thiopurines prevent advanced

Aliment Pharmacol Ther 2014; 39: 645-659 ª 2014 John Wiley & Sons Ltd

colorectal neoplasia in patients with inflammatory bowel disease. Gut 2012; 61: 235–40. 122. Fraser AG, Orchard TR, Robinson EM, Jewell DP. Long-term risk of malignancy after treatment of inflammatory bowel disease with azathioprine. Aliment Pharmacol Ther 2002; 16: 1225–32. 123. Gisbert JP, Linares PM, McNicholl AG, Mate J, Gomollon F. Metaanalysis: the efficacy of azathioprine and mercaptopurine in ulcerative colitis. Aliment Pharmacol Ther 2009; 30: 126–37. 124. Annese V, Daperno M, Rutter MD, et al. European evidence based consensus for endoscopy in

inflammatory bowel disease. J Crohns Colitis 2013; 7: 982–1018. 125. Matsumoto T, Nakamura S, Jo Y, Yao T, Iida M. Chromoscopy might improve diagnostic accuracy in cancer surveillance for ulcerative colitis. Am J Gastroenterol 2003; 98: 1827–33. 126. Lutgens MW, van Oijen MG, van der Heijden GJ, Vleggaar FP, Siersema PD, Oldenburg B. Declining risk of colorectal cancer in inflammatory bowel disease: an updated metaanalysis of population-based cohort studies. Inflamm Bowel Dis 2013; 19: 789–99.

659