Risk of Rectal Neoplasia after Colectomy and Ileorectal Anastomosis for Ulcerative Colitis

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1 Journal of Crohn's and Colitis, 2017, doi: /ecco-jcc/jjx027 Advance Access publication February 21, 2017 Original Article Original Article Risk of Rectal Neoplasia after Colectomy and Ileorectal Anastomosis for Ulcerative Colitis Mathieu Uzzan a, Julien Kirchgesner b, Nadia Oubaya c, Aurélien Amiot d, Jean-Marc Gornet e, Philippe Seksik b, Stéphane Nancey f, Eddy Cotte g, Matthieu Allez e, Gilles Boschetti f, David Laharie h, Nicola de Angelis i, Maria Nachury j, Anne-Laure Pelletier k, Vered Abitbol l, Mathurin Fumery m, Antoine Brouquet n, Anthony Buisson o, Romain Altwegg p, Jacques Cosnes b, Yves Panis q, Xavier Treton a a Department of Gastroenterology, IBD and Nutritive Assistance, Hôpital Beaujon, APHP, Clichy, France b Department of Gastroenterology, Hôpital Saint Antoine, APHP, Paris, France c Department of Epidemiology and Clinical Research, Hôpital Beaujon, APHP, Clichy, France d Department of Gastroenterology, Hôpital Henri Mondor APHP, Créteil, France e Department of Gastroenterology, Hôpital Saint Louis, APHP, Paris, France f Department of Gastroenterology, CHU Lyon Sud, Pierre- Bénite, France g Department of Digestive Surgery, CHU Lyon Sud, Pierre-Bénite, France h Department of Gastroenterology, Hôpital du Haut-Levêque, CHU Bordeaux, Pessac, France i Department of Digestive Surgery, Hôpital Henri Mondor, APHP, Créteil, France j Department of Gastroenterology, CHRU Lille, Lille, France k Department of Gastroenterology, Hôpital Xavier Bichat, APHP, Paris, France l Department of Gastroenterology, Hôpital Cochin, APHP, Paris, France m Department of Gastroenterology, CHU Amiens, Amiens, France n Department of Digestive Surgery, Hôpital du Kremlin-Bicêtre, APHP, France o Department of Gastroenterology, CHU Estaing, Clermont-Ferrand, France p Department of Gastroenterology, CHRU Montpellier, Montpellier, France q Department of Digestive Surgery, Hôpital Beaujon, APHP, France Corresponding author: Mathieu Uzzan, MD, Hopital Beaujon, Service de Gastroentérologie, MICI et Assistance Nutritive, 100 Boulevard du Général Leclerc, Clichy, France. Tel: ; Fax: ; address: mathieuuzzan@gmail.com Abstract Background and Aims: Colectomy can be required in the management of ulcerative colitis [UC]. While ileal-pouch anal anastomosis [IPAA] is the recommended reconstruction technique, ileorectal anastomosis [IRA] is still performed and might present some advantages. However, the risk of rectal neoplasia might limit its indication. The aims of our study were to determine the of rectal neoplasias following IRA for UC and to identify risk factors associated with rectal carcinomas. Methods: We performed a multicenter retrospective study including patients who underwent IRA for UC from 1960 to 2014 in 13 centers. Cox-proportional hazard models were used to determine carcinoma-associated risk factors. Results: A total of 343 patients were included, with a median follow-up of 10.4 years after IRA. At the end of follow-up, 38 rectal neoplasias (including 19 carcinomas) were diagnosed, and 7 patients [2%] had either died from rectal carcinoma or had a metastatic disease. Incidences of rectal carcinoma after IRA for UC were estimated at 3.2% at 10 years and at 7.3% at 20 years, whereas s of Abbreviations: IBD, Inflammatory bowel diseases; IPAA, Ileal pouch anal-anastomosis; IRA, Ileorectal anastomosis; PSC, Primary sclerosing cholangitis; UC, Ulcerative colitis. Copyright 2017 European Crohn s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please journals.permissions@oup.com 930

2 Rectal neoplasia after ileorectal anastomosis in UC 931 neoplasia were estimated at 7.1% and 14% at 10 and 20 years, respectively. In multivariate analysis, age at IRA, IBD duration, primary sclerosing cholangitis [PSC] and history of prior colonic carcinoma were independently associated with the risk of rectal carcinoma following IRA. Conclusion: The risk of rectal carcinoma in patients with IRA for UC remains, and this justifies long-term endoscopic surveillance. Either IPAA or end ileostomy should be considered in highrisk patients i.e. those with PSC and/or with prior colonic neoplasia. Key Words: Ulcerative colitis; ileorectal anastomosis; rectal carcinoma; rectal neoplasia 1. Introduction Despite progress in medical management, colectomy for ulcerative colitis [UC] is still performed in up to 30% of patients. 1 3 It is required in several circumstances, including refractory disease to medical therapy, and colonic neoplasia. 4 Patients with inflammatory bowel diseases with colonic involvement are at higher risk of developing colonic neoplasia compared with the general population. 5 This potentially lethal complication usually necessitates a colectomy. While ileal-pouch anal anastomosis [IPAA] is recommended by the European current guidelines as the preferential reconstruction technique after colectomy for UC, 6,7 ileorectal anastomosis [IRA] appears to have some advantages. The latter include a potentially better functional outcome as well as a less complex surgical procedure. 8 However, the fear of the occurrence of a subsequent neoplasia located on the remnant rectum might limit its indications. To date, only limited knowledge regarding this issue is available, which is gathered in a recent meta-analysis by Derikx et al. 9 The pooled prevalence of rectal neoplasia after colectomy and IRA was 2.4% among 2762 patients, with a reported follow-up ranging from 1 to 35 years. The combined analysis of three widely heterogeneous studies revealed a history of prior colonic carcinoma as a risk factor for developing rectal carcinoma after IRA. 9 Other potential risk factors have never been studied or have been insufficiently studied and reported. Moreover, until recently only one cohort study (including 86 patients) estimated the cumulative of rectal carcinoma after IRA. 10 Therefore, the available evidence regarding the risk of rectal neoplasia after IRA for UC as well as its associated risk factors remains scarce. It is mainly based on historical studies often exhibiting a restricted size cohort, a very variable duration of follow-up, or the occurrence of very few events, thus providing inaccurate and one-dimensional data. To address these important and clinical practice oriented questions, we conducted a retrospective study from a large GETAID/ GETAID chirurgie cohort, and our aim was to determine the of rectal neoplasia after colectomy and IRA for UC and to identify risk factors associated with rectal carcinoma. 2. Methods 2.1. Patients The present cohort of patients has been studied regarding the risk of IRA failure and the results of that study have already been published. 11 The cohort was built from a centralized GETAID/GETAID chirurgie registry. GETAID is a consortium of French and European inflammatory bowel disease [IBD] centers. In the present study, 13 French centers participated and enrolled patients using an online registry. Data were then retrospectively collected from medical records. Colectomies and IRAs were performed from 1960 to 2014, and the last known contact date ranged from 1972 to Patients were followed until secondary protectomy, death or last known contact date. Inclusion criteria were as follows: patients who underwent a subtotal colectomy with IRA as the reconstruction technique; patients should be older than 18 years at cohort entry and should have an established diagnosis of UC or indeterminate colitis at the time of the colectomy. Patients with Crohn s disease diagnosed prior to IRA were excluded. There was no limitation on the date of the colectomy and IRA. As no recommendation regarding the frequency of endoscopic surveillance of the remnant rectum is currently available, the endoscopic surveillance of the remnant rectum was performed according to each center s habits. In French tertiary IBD centers, similarly to colonic surveillance, rectal endoscopy is usually performed every 2 3 years in the presence of IRA. The study was approved by the local ethics committee (the Institutional Review Board [IRB ] of HUPNVS, Paris 7 University, Assistance publique des hôpitaux de Paris [AP-HP]) End points The primary end point was defined by the occurrence of rectal carcinoma after IRA for UC. Secondary end points were the occurrence of rectal neoplasia [including dysplasia and carcinoma] after IRA. The diagnosis of rectal carcinoma was always confirmed via histological assessment. The presence of prior colonic neoplasia was based upon the pathological findings of the surgical specimen after colectomy. Since, over the long duration of the study, many changes in definitions, grading and characterization of lesions have occurred, 12 and, as there is a wide interobserver variability in dysplasia evaluation, 13 low-grade and high-grade dysplasia were merged into a unique variable [i.e. dysplasia ]. Indefinite regarding dysplasia was not considered as dysplasia. The concomitant presence of carcinoma and dysplasia was classified as carcinoma. Pathological features were recorded from pathological reports Statistics Quantitative variables are expressed as median (interquartile range [IQR]). Qualitative variables are given as numbers [percentages]. The comparison of patients baseline characteristics according to the occurrence of rectal neoplasias was performed using Chi-square tests for qualitative variables and with a Student t test for quantitative variables. Cumulative s of neoplasias were assessed using a Kaplan Meier analysis. We used a logrank test to compare survival among various subgroups. In order to identify predictors of rectal carcinoma after IRA, a Cox proportional hazards regression analysis was performed. Variables significant at p < 0.20 in the univariate analysis were entered into a multivariate Cox proportional hazards regression model, with a backward variable elimination procedure to assess the strength of the associations, while controlling for possible

3 932 M. Uzzan et al. Table 1. Baseline characteristics according to the occurrence of rectal neoplasia. Patient with incident rectal neoplasia N = 38 Patient without incident rectal neoplasia N = 305 p Male gender, n [%] 20 [52.6%] 154 [50.5%] 0.80 Indeterminate colitis, n [%] 7 [18.4%] 59 [19.3%] 0.40 Age at IRA [years], median [IQR] 43.1 [ ] 32.0 [ ] 0.02 IBD duration at IRA [years], median [IQR] 5.8 [2 15.8] 2.4 [ ] 0.01 Indication for colectomy, n [%] 0.01 Neoplasia 7 [18.4%] 22 [7.2%] Dysplasia 3 14 Carcinoma 4 8 Refractory disease 16 [42.1%] 101 [33.1%] Severe acute colitis 14 [36.8%] 174 [57%] Other and unknown 1 8 Extraintestinal manifestations, n [%] 12 [31.6%] 92 [34.5%] 1 PSC, n 2 [5.3%] 11 [3.6%] 0.60 IBD, inflammatory bowel disease; IRA, ileorectal anastomosis; PSC, primary sclerosing cholangitis. confounding variables. The results are reported with hazard ratios [HR] and their 95% confidence intervals [95% CIs]. The alpha risk was set at 5% for the statistical significance level. Calculations were performed with SAS version 9.4 [Cary, NC]. 3. Results 3.1. Background characteristics We included 343 patients from 13 centers. The median follow-up after IRA was 10.4 years (IQR [ ]). General baseline characteristics with respect to the occurrence of rectal neoplasia are displayed in Table 1. Of note, in the cohort, 13 patients [3.8%] had primary sclerosing cholangitis [PSC], the overall median age at IRA was 32.4 years (IQR [ ]) and 8.6% of patients were operated on for colonic neoplasia. The IRA was performed in 92 patients before 1990, in 165 patients between 1990 and 2005 and in 86 patients after The frequency of prior colonic neoplasia differed between periods, as it was 1.2% before 1990, 5.6% between 1990 and 2005 and 20.9% after Incidence of rectal neoplasia and rectal carcinoma after IRA During follow-up, 38 patients were diagnosed with rectal neoplasia. Of these, 19 had rectal carcinoma. In the overall cohort, the cumulative estimated of rectal carcinoma was 1.4% (95% CI [ ]), 3.2% (95% CI [ ]) and 7.3% (95% CI [ ]) at 5, 10 and 20 years after colectomy and IRA, respectively. Respective cumulative s of rectal neoplasia after IRA were estimated at 3.5% (95% CI [1.8 6]), 7.1% (95% CI [ ]) and 14.0% (95% CI [ ]) at 5, 10 and 20 years [Figure 1]. Cumulative s of post-ira incidental rectal carcinoma were estimated at 0.4% (95% CI [0 1.2]), 3.1% (95% CI [ ]) and 7.0% (95% CI [ ]) at 10, 20 and 30 years after IBD diagnosis, respectively Characteristics of patients with post-ira incidental rectal carcinoma The characteristics of patients with rectal carcinomas are displayed in Table 2. The median age at the time of the IRA confection was 43.5 years in patients who developed a post-ira incidental rectal Cumulative (%) 20% 15% 10% 5% 0% Any rectal neoplasia Rectal carcinoma Rectal dysplasia Follow up (years) Table 2. Characteristics of patients with post-ira incidental carcinoma. Age at rectal carcinoma [years], median [IQR] Time between IRA and rectal carcinoma [years], median [IQR] Time between IBD diagnosis and rectal carcinoma [years], median [IQR] Figure 1. Cumulative of rectal dysplasia, carcinoma and neoplasia after IRA. N = [ ] 12.1 [ ] 28.8 [ ] carcinoma compared with 32.3 in patients who did not develop a post-ira incidental rectal carcinoma during follow-up [p = 0.09]. Of note, at the time of rectal carcinoma diagnosis, 47% of patients had a concomitant presence of rectal dysplasia. During follow-up, 7 patients [36.9%] had died from their rectal carcinoma or had a metastatic disease [TNM Stage IV] (median follow-up after being diagnosed with rectal carcinoma: 1.5 years IQR [ ]) Risk factors associated with rectal carcinoma First, we performed a univariate Cox model analysis to assess for factors associated with post-ira incidental rectal carcinoma [Table 3].

4 Rectal neoplasia after ileorectal anastomosis in UC 933 Table 3. Univariate and multivariate analysis of factors associated with rectal carcinoma after IRA for UC. The final multivariate Cox model was established after backward elimination of non-significant variables. uhr [95% CI] p ahr [95% CI] p Male gender 1 [ ] 0.94 Age at IRA +10 years 1.7 a [ ] < a [ ] IBD duration at IRA +10 years 1.8 a [ ] < a [ ] IRA period < 1990 Ref [ ] 0.29 > [ ] 0.12 IBD type UC Ref Indeterminate colits 1.2 [ ] 0.80 Active smoker at the time of IRA 0.5 [ ] 0.5 Extraintestinal manifestation 0.9 [ ] 0.88 Primary sclerosing cholangitis 6.1 [ ] [ ] 0.02 Prior colonic neoplasia No Ref Dysplasia 4.2 [ ] [ ] 0.64 Carcinoma 11.4 [ ] < [ ] uhr, unadjusted hazard ratio; ahr, adjusted hazard ratio; IRA, ileorectal anastomosis; ref, reference variable; UC, ulcerative colitis. a Hazard ratios for a 10- year increase, e.g. age at IRA: ahr = 1.6-fold increase in the risk of post-ira rectal carcinoma for a 10-year increase in age at the time of IRA, 95% CI [ ]. As previous colonic neoplasia appeared as an associated factor for rectal carcinoma after IRA, we assessed the cumulative s of rectal carcinoma and rectal neoplasia according to the presence/ absence of a history of colonic dysplasia or carcinoma. The 10-year estimated cumulative of rectal neoplasia was 30.0% [95% CI [ ]) for patients with previous colonic dysplasia, 50.5% (95% CI [ ]) for patients with previous colonic carcinoma and 6.0% (95% CI [ ]) for patients without previous colonic neoplasia Figure 2. Regarding the risk of rectal carcinoma, the cumulative at 10 years after IRA was estimated at 25.0% (95% [CI ]), 50.5% (95% CI [ ]) and 2.1% (95% CI [ ]) for patients with previous colonic dysplasia, carcinoma or without previous colonic neoplasia, respectively [Figure 3]. Further, using a multivariate Cox model after backward elimination of non-significant variables, we determined that age at IRA, IBD duration, PSC, as well as the history of prior colonic carcinoma at the time of the colectomy, were independently associated with the risk of developing a rectal carcinoma after colectomy and IRA [Table 3]. In multivariate analysis, the period of the IRA confection was not associated with the risk of rectal carcinoma (<1990 as Cumulative of neoplasia (%) 100% 75% 50% 25% 0% No neoplasia at colectomy Dysplasia at colectomy Carcinoma at colectomy Follow up (years) Cumulative of carcinoma (%) 60% 55% 50% 45% 40% 35% 30% 25% 20% 15% 10% 5% 0% Figure 2. Cumulative of rectal neoplasia after IRA according to prior colonic status at colectomy. Logrank tests: Dysplasia at colectomy versus carcinoma at colectomy : p = 0.66; Dysplasia at colectomy versus no neoplasia at colectomy : p = 0.002; Carcinoma at colectomy versus no neoplasia at colectomy : p < No neoplasia at colectomy Dysplasia at colectomy Carcinoma at colectomy Follow up (years) Figure 3. Cumulative of rectal carcinoma after IRA according to prior colonic status at colectomy. Logrank tests: Dysplasia at colectomy versus carcinoma at colectomy : p = 0.17; Dysplasia at colectomy versus no neoplasia at colectomy : p = 0.08; Carcinoma at colectomy versus no neoplasia at colectomy : p <

5 934 M. Uzzan et al. reference; ahr = 1, 95% CI [ ] for ; ahr = 0.8, 95% CI [ ] after 2005). 4. Discussion In the present study, we report an overall cumulative of rectal carcinoma at 3.2% at 10 years and at 7.3% at 20 years following IRA for UC. Age, IBD duration, PSC, and a prior colonic carcinoma were independently associated with a higher risk. These results were based on a multicenter cohort with a long median follow-up of >10 years. Therefore, the high number of reported rectal carcinomas [19 events] makes our findings accurate and reliable regarding estimated long-term s and risk factors. Previously reported cumulative s are detailed in Table 4. Abdalla et al. recently reported the data from a Swedish nation-wide population-based study. They estimated the cumulative s of rectal carcinoma at 1.6% at 10 years and at 5.6% at 20 years after IRA for UC. 14 Regarding the estimated s according to IBD duration, in the metaanalysis of Derikx et al. (a pooled analysis of three studies), the long-term estimations of of post-ira rectal carcinoma were higher than those in our study: 0%, 5% and 10% compared with 0.4%, 3.1% and 7% at 10, 20 and 30 years after IBD diagnosis, respectively. 9 In our study, the large number of patients followed for a long period of time may explain that the long-term s that we observed were not over-estimated, which could be the case in smaller cohorts, particularly with a shorter follow-up. Conversely, our numbers might be overestimated compared with population-based studies as our study mainly involved more severe patients followed in tertiary centers. However, our cohort may be able to provide more accurate, deeper insights regarding risk factors. Regarding the risk of carcinoma following IPAA and as expected, the overall cumulative of pouch carcinoma after IPAA is lower than the risk of rectal carcinoma after IRA. It has been reported by Derikx et al. at 1.4% at 10 years and at 3.3% at 20 years after IPAA confection. 15 Interestingly, it was estimated at 0.1% at 10 years and at 0.1% at 20 years in the Swedish population-based study. 14 Unfortunately, we couldn t compare the of rectal cancer following IRA with the of pouch carcinoma following IPAA in a complementary GETAID cohort, as this is currently not available. Similarly to the risk for colonic carcinoma in the context of inflammatory colitis, 5 we determined that age and disease duration at the time of IRA as well as the concomitant presence of PSC were independently associated with the risk of developing rectal carcinoma after IRA for UC. PSC is thus highly associated with the risk of colorectal carcinoma in the context of IBD, before as well as after colectomy. This may also be the case in the context of IPAA. 16 It has been stated that endoscopic surveillance is required in the context of IRA for UC. 5,17,18 However there are no current guidelines available regarding the recommended frequency. The earliest rectal carcinoma occurred after 9.7 years of IBD duration in our cohort and, similarly to what it is recommended for colon screening in IBD, a rectal endoscopy screening doesn t seem necessary in the early years of the disease. Conversely, we observed the earliest rectal carcinoma 1 year after the IRA confection, so rectal neoplasia screening might be required even a short time after IRA. A reasonable approach for a screening strategy would be to follow current guidelines regarding colonic screening in IBD i.e. based on IBD duration. The relatively low overall risk of rectal carcinoma in the absence of risk factors may allow rectal endoscopies to be performed every 2 to 3 years. Table 4. Previously reported cumulative s of rectal carcinoma following colectomy and IRA for UC. Incidences of post IRA rectal carcinoma after IBD diagnosis Incidences of rectal carcinoma after IRA Follow-up [years] Number of rectal carcinomas Study [First Author, Journal, Year of publication] Number of patients 30-year 20-year 10-year 20-year 10-year Baker, Br J Surg, [5.9%] - 0% 6% 15% Grundfest, Ann Surg, [4.8%] 7.7 [mean] 0.5% 0.9% 3.4% da Luz Moreira, Br J Surg, [8.1%] 11 [median] 2% 14% Andersson, J Crohns Colitis, [1.9%] 5.4 [mean] 0% 2.1% Abdalla, Clin Gastroenterol Hepatol, [1.8%] 8.6 [mean] 1.6% 5.6% Data from our cohort [5.5%] 10.4 [median] 3.2% 7.3% 0.4% 3.1% 7% IBD, inflammatory bowel diseases; IRA, ileorectal anastomosis.

6 Rectal neoplasia after ileorectal anastomosis in UC 935 However in the presence of risk factors, including PSC and prior colonic neoplasia, a higher frequency of rectal surveillance seems necessary. Nevertheless, either IPAA or end ileostomy should be considered as the preferential approach after colectomy for UC in patients presenting such risk factors for colorectal carcinoma. Unfortunately, we were not able to determine whether other known colonic carcinoma associated factors for IBD, such as chronic inflammation and the use of treatments, influence the risk of rectal carcinoma after IRA. Additional studies are warranted for assessing these factors in order to determine a more tailored approach for rectal surveillance after UC. While our study provides informative findings regarding the risk of rectal neoplasias after IRA for UC, some limitations have to be discussed. First, grading of dysplasias and centralized pathologic examinations have not been performed. As exposed in the Materials and Methods section, the wide period of the study did not allow us to do this. However, we selected a strong primary end point, i.e. rectal carcinoma, and we considered separately colonic dysplasia and colonic carcinoma for the risk factor analysis, which make our findings reliable. Second, data regarding surveillance [i.e. frequency and number of rectal endoscopies] was not available. Additionally, the long follow-up as well as the large number of patients followed in expert IBD centers are strong features of our cohort. 5. Conclusion Rectal carcinoma may develop at a clinically relevant rate in UC patients with IRA, and this may justify regular endoscopic surveillance. The risk of rectal carcinoma is raised by a history of colonic neoplasia, IBD duration, age, and an associated diagnosis of PSC. UC patients with IRA who present one or several of the latter risk factors should be closely monitored for the risk of rectal carcinoma. Moreover, given the high risk of rectal neoplasia, either IPAA or end ileostomy should be viewed as the preferred option after colectomy for patients with PSC and/or prior colonic neoplasia, along with necessary endoscopic pouch surveillance. Funding None. Conflict of Interest None related to this work. Acknowledgments This study was conducted on the behalf of the GETAID and the GETAID chirurgie groups. We would like to thank the following physicians and surgeons involved in this study: Jean-Louis Dupas, Jean-Marc Regimbeau, Charles Sabbagh [CHU Amiens], Gilles Bommelaer, Anne Dubois [Clermont-Ferrand, CHU Estaing], Yoram Bouhnik, Carmen Stefanescu, Léon Maggiori [Clichy, Hôpital Beaujon], Nicolas de Angelis, Francesco Brunetti [Créteil, Hôpital Henri Mondor], Franck Carbonnel, Stéphane Benoist [Kremlin-Bicêtre], Benjamin Pariente, Philippe Zerbib, Guillaume Piessen [CHRU Lille], Lara Ribeiro [Paris, Hôpital Bichat], Mahaut Leconte, Bertrand Dousset [Paris, Hôpital Cochin], Harry Sokol, Laurent Beaugerie, Jérémie Lefevre, Emmanuel Tiret [Paris, Hôpital Saint-Antoine], Clotilde Baudry, Nicolas Munoz-Bongrand [Paris, Hôpital Saint-Louis], Quentin Denost [Pessac, CHU Bordeaux], Bernard Flourie [Pierre-bénite, CHU Lyon-Sud], Françoise Guillon, Guillaume Pineton de Chambrun, Jean-Michel Fabre [Montpellier]. References 1. Farmer RG, Easley KA, Rankin GB. 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