Review article: the incidence and prevalence of colorectal cancer in inflammatory bowel disease

Aliment Pharmacol Ther 23; 18 (Suppl. 2): 1 5. Review article: the incidence and prevalence of colorectal cancer in inflammatory bowel disease P. MUNKHOLM Department of Medical Gastroenterology, Hvidovre University Hospital,, Denmark SUMMARY Although colorectal cancer (CRC), complicating ulcerative colitis and Crohn s disease, only accounts for 1 2% of all cases of CRC in the general population, it is considered a serious complication of the disease and accounts for approximately 15% of all deaths in inflammatory bowel disease (IBD) patients. The magnitude of the risk was found to differ, even in population-based studies. Recent figures suggest that the risk of colon cancer for people with IBD increases by.5 1.% yearly, 8 1 years. The magnitude of CRC risk increases with early age at IBD diagnosis, longer duration of symptoms, and extent of the disease, with pancolitis having a more severe inflammation burden and risk of the dysplasiacarcinoma cascade. Considering the chronic nature of the disease, it is remarkable that there is such a low incidence of CRC in some of the population-based studies, and possible explanations have to be investigated. One possible cancer-protective factor could be treatment with 5-aminosalicylic acid preparations (5-ASAs). Adenocarcinoma of the small bowel is extremely rare, compared with adenocarcinoma of the large bowel. Although only few small bowel cancers have been reported in Crohn s disease, the number was significantly increased in relation to the expected number. INTRODUCTION Patients with inflammatory bowel disease (IBD) are at an increased risk of developing colorectal cancer (CRC). 1 4 Although CRC, complicating ulcerative colitis and Crohn s disease, only accounts for 1 2% of all cases of CRC in the general population (Figure 1), it is considered a serious sequela of the disease and accounts for one in six of all deaths in IBD patients. 3, 5 Most cases of CRC are either sporadic (65 85%) or familial (1 3%) (Figure 1). 3, 4 The magnitude of CRC risk increases with early age at IBD diagnosis, longer duration of symptoms, and severity of inflammation and dysplasia. The results of clinical studies vary, but recent figures suggest that the Correspondence to: Dr Pia Munkholm, Department of Medical Gastroenterology, Hvidovre Hospital, University of, Kettegård Allé 3, DK-265 Hvidovre, Denmark. E-mail: pia_munkholm@mail.dk risk of colon cancer for people with IBD increases by 4, 6, 7.5 1.% yearly, 8 1 years. Compared with age-matched controls, approximately 5 1% of IBD patients develop colon cancer after 2 years and 12 2% after 3 years of disease. 1, 5 The mean age of developing CRC in IBD is lower than for sporadic CRC (4 5 vs. 6 years). Patients with disease only in the rectum have the lowest risk, and having only part of the colon involved carries an intermediate risk. The greatest risk is for people whose entire colon is diseased (pancolitis). However, colon cancer does not distinguish between active disease and remission. Patients whose disease has been quiescent have the same risk as those who have a more active disease course. Considering the pathology and the chronic nature of IBD, the incidence of CRC is remarkably low from these population-based studies. Therefore, possible explanations have to be examined. Ó 23 Copyright Blackwell Publishing Ltd 1

2 P. MUNKHOLM Familial 1 3% Sporadic 65 85% Hereditary nonpolyposis CRC (HNPCC) 5% Familial adenomatous polyposis (FAP) 5% Rare CRC syndromes.1% % patients 7 6 5 4 3 2 1 M: 8.5 years M: 11.5 years Total 5-ASA Continuous 5-ASA Intermittent 5-ASA UC/CD related CRC 2% Figure 1. Prevalence and aetiology of colorectal cancer (CRC) in the general population. 3, 4 CD n = 373 UC n = 1161 PREVALENCE OF COLORECTAL CANCER IN INFLAMMATORY BOWEL DISEASE Ulcerative colitis and colorectal cancer Both ulcerative colitis and Crohn s disease carry an increased risk of CRC, although more is known about ulcerative colitis. In a meta-analysis, the overall prevalence of CRC in any ulcerative colitis patient, based on 116 studies, was estimated to be 3.7% (95% CI 3.2 4.2%). 7 The incidence rate corresponded to cumulative probabilities of 2% by 1 years, 8% by 2 years, and 18% by 3 years (Figure 2). 7 Over time, the cancer risk has increased since 1955 but this finding was not significant (P ¼.8). Figures for the incidence of CRC in ulcerative colitis were significantly less in a Danish population study (n ¼ 1161):.2% after 1 years, 1.4% after 2 years and 3.1% by 3 years (Figure 2). 2, 8 However, it should be emphasized that the majority of the IBD patients (7%) were receiving regular anti-inflammatory therapy (sulfasalazine [SASP] 5-aminosalicylic acid [5-ASA]) (Figure 3), 9 and that these cancer chemopreventative agents could explain the overall low risk of CRC that was seen in the cohort. 1 The low cancer risk in ulcerative colitis found in the study might additionally be explained by the high surgery rate, i.e. removal of the target at risk. 8 Indeed, it was determined Cumulative probability (%) 25 2 15 1 5 5 1 15 2 25 3 Time from diagnosis (years) Upper CL Cumulative risk of CRC Lower CL 1962 97 Figure 2. Cumulative risk of developing colorectal cancer (CRC) 2, 7, 8 in ulcerative colitis. Figure 3. Percentage of patients with inflammatory bowel disease receiving 5-ASA in the Danish Cohort, 1962 87. 9 that all ulcerative colitis patients were at risk as long as they had not undergone colectomy. After colectomy, patients were withdrawn from the reckoning as not being at risk and were considered cured. 5-aminosalicylic acid number needed to treat According to the Cochrane reviews by Sutherland et al. the number needed to treat (NNT) in ulcerative colitis to obtain one clinical remission or endoscopic remission was 12 and 11, respectively, and to maintain remission the NNT was 6. In Crohn s disease, the advantage of 5-ASA treatment has been questioned, although post-operative ileal Crohn s disease seems to benefit from maintenance 5-ASA treatment (NNT ¼ 1). The NNT to avoid one CRC after 1 years was 63, 15 after 2 years and 7 after 3 years, respectively (Table 1). The cohort ulcerative colitis population, 8 of whom 7% had received 5-ASA and or surgery, has been compared with patients from Dr Eaden s meta-analysis 7 from 116 different centres using various treatment stategies (not mentioned). It is likely that the cohort in general probably had a higher number of patients (7%) treated with 5-ASA compared with a lower number in the meta-analysis. We then compared the probability rates of developing CRC from the data 8 with the risk of developing CRC in the meta-analysis: 7.4% vs. 2% after 1 years, 1.5% vs. 8% after 2 years and 3.4% vs. 18% after 3 years, repectively and then estimated the NNT with 5-ASA to prevent CRC (Table 1). Crohn s disease and colorectal cancer and adenocarcinoma of the small bowel As in ulcerative colitis, Crohn s disease of the colon carries an increased risk of CRC. The magnitude of the Ó 23 Copyright Blackwell Publishing Ltd, Aliment Pharmacol Ther 18 (Suppl. 2), 1 5

INCIDENCE AND PREVALENCE OF CRC IN IBD 3 Table 1. Number needed to treat (NNT) with 5-ASA to avoid colorectal cancer (CRC) over time. Estimated rate of CRC in the Danish cohort 2, 8 if figures in the noncompliant 5-ASA group are applied from Eaden et al. 7 The NNT values are from this estimated calculation Treatment 1 years 2 years 3 years Cumulative incidence rates of CRC in UC: With 5-ASA (7%) 2, 8.4% 1.5% 3.4% Without 5-ASA 7 2% 8% 18% Relative risk reduction 8% 81% 81% Absolute risk 1.6% 6.5% 14.6% NNT to avoid one case of CRC 1 1.6 ¼ 62.5 1 6.5 ¼ 15.3 1 14.6 ¼ 7 CRC: colorectal cancer; UC: ulcerative colitis; NNT: number needed to treat. Risk of development of CRC in a meta-analysis of 116 studies of ulcerative colitis patients. Number needed to treat modified after Eaden et al. 7 risk however, differs even in population-based studies. Ekbom et al. 1 found a relative risk (RR) of 5.6 for CRC among patients with Crohn s colitis, whereas in another Swedish patient cohort study, Persson et al. 11 did not find the population-relative risk increased. Similarly, Fireman et al. 12 from Israel and Jess et al. 13 in the Danish cohort, did not find an increased risk of CRC among their patients with Crohn s disease (Figure 4). The Danish population-based cohort, comprising 374 patients with Crohn s disease diagnosed in County between 1962 and 1987, was observed until 1997. 14 Cancer in the small and or large bowel occurred in three patients vs. an expected 1.8 (P ¼ NS). NS). Small bowel cancer was found in two patients vs..4 expected (P ¼.1). The life-time risk of intestinal cancer was similar; 4.1% compared with 3.8% for the Danish population in general (P ¼ NS). Overall, the life-time risk of cancer in patients with Crohn s disease was not found to be increased, although the risk of rare small bowel cancer was significantly elevated after 25 years of observation time and further increased at 35 years (RR of 5 at 25 years [two patients] vs. 66 after 35 years [four patients]). Adenocarcinoma of the small bowel is extremely rare, compared with adenocarcinoma of the large bowel. Although only few small bowel cancers have been reported in Crohn s disease, the number has significantly increased in relation to the expected number in some parts of the world, and RRs have been found to be 16, 4, 5 and 66 in studies from Sweden, 11 the UK 15 and Denmark 13, 14 (Figure 5). Colorectal cancer in Crohn s disease or ulcerative colitis From the study of Gillen et al. however, it appears that the malignant potential in Crohn s colitis and ulcerative colitis is of the same order of magnitude. 15 They compared directly the CRC risk in patients with extensive ulcerative colitis (n ¼ 486) and patients with extensive Crohn s colitis (n ¼ 125), extracted from their previously published series from Birmingham, 3.5 3.4 7 66 Relative risk 3 2.5 2 1.5 1.1 1.14 1.89 2. 2.5 Relative risk 6 5 4 3 2 4 15.6 5.5 Stockholm Israel Olmsted Uppsala Birmingham 1 Israel Olmsted Stockholm Birmingham Figure 4. Prevalence of cancer in the large bowel in patients with Crohn s disease. 11 15 Figure 5. Prevalence of cancer in the small bowel in patients with Crohn s disease. 11 15 Ó 23 Copyright Blackwell Publishing Ltd, Aliment Pharmacol Ther 18 (Suppl. 2), 1 5

4 P. MUNKHOLM UK. The cumulative risk for developing CRC was 7% after 2 years for ulcerative colitis and 8% for Crohn s colitis, an increase of 18- and 19-fold compared with the background population of similar age and gender. In a further study, Choi and Zelig compared 8 patients with concomitant CRC, from 3124 patients with Crohn s disease and 393 with ulcerative colitis. 3 During the same period, 5266 patients with CRC but without IBD were seen in the clinic. The cancers in ulcerative colitis and Crohn s disease occurred as a median, 15 and 18 years after onset of IBD. The tumours were multiple in 11 and 12%, respectively, and occurred in connection with dysplasia in 73% and 79%, respectively. The histological picture was very similar in the two diseases. Five-year survival rates were 46% and 5%, respectively. Cancers developed in inflamed areas, in both diseases and were thus located in the right colon in 49% in patients with Crohn s disease, compared with 36% in ulcerative colitis, reflecting the difference in inflammatory sites in the two diseases. Adenocarcinomas develop only in affected segments of the small intestine, and are difficult to diagnose at an early stage because the radiological appearance is similar to that of stricturing Crohn s disease. Proper surveillance is thus difficult or impossible, but this should be kept in mind when surgery for a small bowel segment with Crohn s disease or continuous prophylactic 5-ASA treatment with respect to cancer chemoprevention is considered. MORTALITY The mortality in patients diagnosed with CRC in the patients with IBD is higher than for sporadic CRC. 16 The Danish population-based cohort, comprising 374 patients with Crohn s disease between 1962 and 1987 14 was observed until 1987 and further extended until 1997 for mortality and causes of death. 17 A total of 84 deaths (45 women, 39 men) occurred vs. 67 expected (standardized mortality ratio [SMR], 1.3; 95% confidence interval [CI], 1.1 1.56). Fourteen (31%) of the observed deaths among women and eight (21%) among men, had a certain or possible connection to Crohn s disease. Nine Crohn s disease patients had gastrointestinal cancer (four with colon cancer, four with adenocarcinomas of the small bowel and one with gastric cancer). Three out of four patients with adenocarcinoma of the small bowel died, three out of four with colon cancer died due to metastatic CRC. Overall, an increased mortality was observed late in the disease course that was most pronounced among women younger than 5 years at diagnosis and was attributed to death associated with severe Crohn s disease. RISK FACTORS The major risk factors for the development of CRC include: young age at onset of IBD (RR ¼ 2 if < 3 years at diagnosis), 1 extensive disease (RR ¼ 1.7 proctitis; 2, 18 RR ¼ 2.8 left sided; RR ¼ 14.8 pancolitis), longdisease duration (RR ¼ 5 19), primary sclerosing 2, 19 cholangitis (PSC) (RR ¼ 9 18), 2 22 and genetic susceptibility (RR ¼ 2 26). 23, 24 Thus, surveillance should especially be addressed to these sub-populations at risk. There is also an increased risk of colonic cancer in patients diagnosed with ulcerative colitis before 1965 (RR ¼ 8.1) and a lesser risk after 1965 (RR ¼ 4.). 1 Therefore, the natural disease course has changed over time as medical and surgical techniques have improved. It is likely that the combined efforts of medical treatment and timing of surgery account for the better prognosis. Although only three Crohn s disease patients out of 373 diagnosed during 1962 87, followed for a median of 11.5 years ( 25 years), developed intestinal cancer, certain subpopulations of Crohn s disease patients have been shown to carry an increased risk of CRC. In Crohn s disease with long-disease duration, the RR was 4.8 (P ¼.1) and in long-standing cases where no surgery had been performed the RR increased further (RR ¼ 8.3; P ¼.5). 19 A familial association also exists between CRC in ulcerative colitis patients and with CRC in the general population. 2 Colorectal cancer in ulcerative colitis patients represents a risk factor for CRC in noncolitic relatives and a family history of sporadic CRC increases the risk of CRC with ulcerative colitis. In another study, CRC rates among first-degree relatives of patients with IBD were assessed to determine whether an association between the two diseases existed. 23 Colorectal cancer in persons with ulcerative colitis represented a risk factor for CRC in their noncolitic relatives. Likewise, a family history of sporadic CRC increased the risk of CRC with ulcerative colitis. CONCLUSIONS Sporadic CRC is one of the commonest forms of carcinoma, thus everyone is at some degree of risk, whether IBD is present or not. However, for both ulcerative colitis Ó 23 Copyright Blackwell Publishing Ltd, Aliment Pharmacol Ther 18 (Suppl. 2), 1 5

INCIDENCE AND PREVALENCE OF CRC IN IBD 5 and Crohn s colitis, the results of epidemiological studies suggest the risk of developing CRC increases with disease duration, young age at diagnosis, extent of disease, PSC and a familial association. Small-bowel cancer is also rare in patients with IBD, however, patients with Crohn s disease are at increased risk for this type of cancer. Despite the increased RR in Crohn s disease, the absolute number of patients at risk is relatively small. Patients with extensive colitis in Crohn s disease and ulcerative colitis undergo a colectomy with a frequency of 15 2% within 15 years from the initial diagnosis. 9 Limited resection in patients with Crohn s disease carries a probability of 5% within 15 years from the diagnosis. It is therefore proposed that to prevent cancer development in the intestine of patients with IBD the combined use of medical treatment and the timing of surgery account for a better prognosis. With respect to the incidence of cancer in IBD and how it can be prevented Dr Vibeke Binder recommended that: it seems from the literature that the close clinical follow-up, maintenance treatment with 5-ASA preparations, early use of steroids in flare-up episodes, and colectomy in treatment failures may reduce this risk. Such a management regimen should thus be recommended. 25 REFERENCES 1 Ekbom A, Helmick C, Zack M, et al. Increased risk of large bowel cancer in Crohn s disease with colonic involvement. Lancet 199; 336: 357 9. 2 Langholz E, Munkholm P, Davidsen M, et al. Colorectal cancer risk and mortality in patients with ulcerative colitis. Gastroenterology 1992; 13: 1444 51. 3 Choi PM, Zelig MP. Similarity of colorectal cancer in CD and UC. Implications for carcinogenesis and prevention. Gut 1994; 35: 95 4. 4 Gyde S, Prior P, Dew MJ, Saunders V, Waterhouse JA, Allan RN. Mortality in ulcerative colitis. Gastroenterology 1982; 83: 36 43. 5 Lennard-Jones JE. 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