ORIGINAL CONTRIBUTION
Prediction of Need for Surgery After Endoscopic Balloon Dilation of Ileocolic Anastomotic Stricture in Patients With Crohn’s Disease Lei Lian, M.D., Ph.D.1,2 • Luca Stocchi, M.D.1 • Bo Shen, M.D.2 • Xiaobo Liu, M.S.3 Jessica Ma2 • Brook Zhang2 • Feza Remzi, M.D.1 1 Department of Colorectal Surgery, Cleveland Clinic, Cleveland, Ohio 2 Department of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, Ohio 3 Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland, Ohio
BACKGROUND: Endoscopic balloon dilation is used to treat ileocolic anastomotic stricture attributed to recurrent Crohn’s disease. OBJECTIVE: The purpose of this work was to investigate long-term outcomes after dilation of ileocolic anastomotic stricture and to identify risk factors associated with the need for subsequent surgical intervention. DESIGN: This was a retrospective study based on chart review of an electronic medical chart system. SETTINGS: The study was conducted at a tertiary care
center. PATIENTS: All of the eligible patients with ileocolic anastomotic stricture attributed to recurrent Crohn’s disease treated with endoscopic dilation between December 1998 and May 2013 were evaluated. Patients with concurrent enterocutaneous fistula or abdominal or pelvic abscess were excluded. MAIN OUTCOME MEASURES: The main outcome measure was the need for subsequent salvage surgery because of stricture-related symptoms. Funding/Support: Dr Stocchi was partially supported by the Story Garschina Endowed Chair.
RESULTS: A total of 185 patients with Crohn’s disease (45.9% women; mean age, 43.1 years; symptomatic strictures in 80%) underwent 462 endoscopic dilations of ileocolic anastomosis (median per-patient dilations, 2; range, 1–3). During a mean follow-up of 3.9 years, 27 patients (14.6%) required hospitalization without surgery for stricture-related symptoms, and 66 patients (35.7%) required subsequent salvage surgery. Specific medical management, type of anastomosis, and endoscopic intralesional steroid injection had no impact on the risk of needing surgery. Significant factors associated with the need for surgery on multivariable analysis were symptomatic disease (HR, 3.54 [95% CI, 1.41–8.93]), longer time interval from last surgery (HR, 1.05 [95% CI, 1.01–1.10]), and radiographic proximal bowel dilation (HR, 2.36 [95% CI, 1.38–4.03]). A nomogram estimating the need for surgery was created with a concordance index of 0.67. LIMITATIONS: The study was limited by its retrospective
design. CONCLUSIONS: Although endoscopic dilation is a valid option for ileocolic anastomotic stricture attributed to recurrent Crohn’s disease, the need for surgery is common. The nomogram can identify patients who might benefit from upfront surgery.
Financial Disclosure: None reported. Podium presentation at the meeting of The American Society of Colon and Rectal Surgeons, Hollywood, FL, May 17 to 21, 2014. Correspondence: Luca Stocchi, M.D., Desk A 30, Department of Colorectal Surgery, Cleveland Clinic, 9500 Euclid Ave, Cleveland, OH 44195. E-mail: [email protected] Dis Colon Rectum 2015; 58: 423–430 DOI: 10.1097/DCR.0000000000000322 © The ASCRS 2015 Diseases of the Colon & Rectum Volume 58: 4 (2015)
KEY WORDS: Anastomotic stricture; Crohn’s disease; Endoscopic balloon dilation; Nomogram; Prediction.
C
rohn’s disease (CD) is a chronic disease most commonly affecting the terminal ileum. It is estimated that ≤80% of patients with CD require surgical treatment at some point,1 most commonly ileocolic resection to treat CD-related strictures.2 However, the recurrence rate is high after ileocolic resection and may occur 423
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at the anastomotic site or in the neoterminal ileum.3,4 The cumulative probability of clinical recurrence is estimated at ≈10% per year.5 As recurrent disease progresses, anastomotic stricture may ensue and lead to bowel obstruction. The benefit of medical therapy in this setting is limited6 because of the mechanical nature of stricture, and surgical resection with reanastomosis is often required. Consequently, one fourth of the patients will require a second operation by 4 years, and approximately one-half by 10 to 15 years.7–9 Endoscopic through-the-scope balloon dilation (EBD) of the strictures has emerged as an effective alternative in patients with CD stricture,10 particularly for short and isolated strictures at the ileocolic anastomosis (ICA), which are often linear11 and may appear in the complete absence of disease recurrence.12 Although anastomotic strictures can be more technically challenging than de novo strictures,13 anastomotic strictures may also be associated with improved long-term outcomes when compared with de novo strictures.14 Currently, the majority of studies summarizing the outcomes of EBD of CD strictures have either a relatively small sample size with short follow-up or include both primary and secondary (anastomotic) strictures.10 Few studies have specifically focused on ICA.15 In addition, data pertaining to factors associated with long-term success as defined by the need for subsequent surgical resection after EBD for ICA stricture in patients with CD remain sparse.10,16–18 The aims of this study were, therefore, to analyze long-term outcomes after EBD for ICA stricture in patients with CD in a single institution and to identify variables observable at initial EBD that were risk factors for subsequent salvage surgery to treat ICA stricture attributed to recurrent CD.
PATIENTS AND METHODS Patients
The study was approved by the institutional review board at the Cleveland Clinic. A historical cohort of eligible patients with ICA stricture treated with EBD between December 1998 and May 2013 were evaluated. Inclusion Criteria and Exclusion Criteria
Patients were identified from an electronic health record (EHR; Epicsys, Verona, WI). Inclusion criteria for the study were patients seen in our IBD center and having a diagnosis of CD (International Classification of Diseases, Ninth Revision, Clinical Modification, code 555.9) documented on EHR and EBD in our billing database. This information was then confirmed by reviewing electronic charts. Clinical notes and endoscopy reports were reviewed to confirm EBD of ICA and to exclude patients with dilation of primary stricture. Patients with ileorectal anastomosis were excluded.
Lian et al: Crohn’s Anastomotic Stricture Dilation
Demographic and Clinical Variables
Demographics (age, sex, and race) were extracted from the EHR. Clinical, endoscopic, histologic, and radiographic data were collected by chart review. Collected data included age at diagnosis, age at the time of treatment, duration of CD (time interval between diagnosis of CD and EBD of ICA stricture), symptoms, smoking history (never, current, or ex-smoker), presence of extraintestinal manifestations, and date of most-recent follow-up. CD medications within the 3 months before EBD were categorized into 5-aminosalicylates, immunomodulators, steroids (oral or intravenous corticosteroids), or biologics. Escalation of medical therapy was defined as use of increased dosage of the same drug or use of a higher class of CD medication after EBD as compared with that before EBD. Endoscopy reports were reviewed to extract data on stricture length, presence and location of concurrent stricture, balloon size, use of intralesional steroid injection, and immediate complications (major bleeding, perforation, or death). Imaging reports within the 3 months preceding EBD (CT, CT enterography, magnetic resonance enterography, or barium studies) were reviewed to determine stricture length and the presence of proximal bowel dilation. Concurrent stricture was defined as the presence of additional stricture(s) other than the ICA stricture located elsewhere in the ileum, jejunum, or colon. Indications and Technique of Endoscopic Balloon Dilation
The decision to perform EBD generally followed the diagnosis of ICA stricture based on clinical presentation and imaging studies. However, EBD could also be performed on ICA strictures that were incidentally encountered in the course of a routine surveillance colonoscopy at the discretion of the endoscopist. Anastomotic or preanastomotic strictures >4 cm and known fistulizing abdominal CD were considered to be not amenable to EBD or as contraindications to EBD in our practice. The procedure was typically done by IBD specialists or therapeutic endoscopists at our institution. Once the stricture was endoscopically visualized, the through-the-scope controlled radial expansion dilating balloon was passed through the biopsy channel through the stricture. The balloon diameter ranged between 12 and 20 mm. Once in place, the balloon was inflated with water using a stepwise approach. The pressure was monitored closely by the assistant throughout the procedure. The pressure was maintained for a few seconds, and then the balloon was deflated. The process could be repeated several times during the same procedure until an adequate visualization of the lumen was achieved unless an angulation or narrow stricture prohibited the passage of the colonoscope. Specific balloon size and endoscopic dilation technique were left at the discretion of the individual endoscopist.
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Outcome Measurements Primary outcome was the need for salvage surgery to treat the ICA stricture because of recurrent CD. Other outcomes, including immediate technical failure, repeated dilation, stricture-associated emergency department visit, hospitalization, and escalation of medical therapy to immunomodulators/biologics were also examined. Major complications were defined as perforation, excessive bleeding requiring transfusion, and death. Technical failure was defined as an inability to pass the endoscope through the anastomosis after dilation. Patient follow-up started from the date of the first EBD until the date of the primary outcome or censoring at the date of the most recent contact. Patients and/or treating physicians were contacted via telephone if no follow-up data were retrievable from our medical charts. Statistical Analysis
Descriptive statistics included means and SDs or medians and interquartile ranges for continuous variables and frequencies and percentages for categorical variables. Univariable analysis was performed using the χ2 and Fisher exact tests (if expected cell counts were less than 5) for categorical study variables, and Student t tests and Wilcoxon ranksum tests were used for continuous variables. Kaplan-Meier analysis was used to calculate the long-term risk of surgical resection to treat ICA strictures. The multivariable Cox proportional hazards model using backward variable selection (ie, step-down method) was used to identify risk factors identifiable at the time of the initial EBD associated with the requirement of surgery adjusting for confounding factors. A number of different combinations among the examined variables were tested for possible interactions, in particular among the independent factors associated with the need for salvage surgery in the final multivariable model. Restricted cubic splines were used for continuous variables to take care of possible nonlinearity of continuous predictors. The nonlinearity terms were removed from the model when shown to be unnecessary. Differences were considered to be statistically significant when a p value was 0) on initial EBD, technique used in the construction of the ICA, and endoscopic steroid injection had no relationship with the risk of having surgery (Table 1). Subgroup Analysis of Patients With Available Imaging Data
Radiographic examination within 3 months before initial EBD was performed in 129 patients, including CT (n = 98), magnetic resonance (n = 12), small-bowel series (n = 16), and abdominal plain film (n = 3). The evaluation of possible associations between radiographic features and the need for subsequent surgery is also included in Table 1. In a subgroup analysis, patients with bowel
dilation proximal to ICA stricture and concurrent bowel stricture elsewhere had a significantly increased risk of requiring salvage surgery. Multivariable Cox Regression Model for Risk of Subsequent Surgery and Development of a Nomogram
A Cox regression model was performed to assess the risk factor for subsequent surgery (Table 2). Significant factors associated with the requirement of surgery on multivariable analysis were symptomatic disease, longer interval from last surgery, and presence of proximal bowel dilation on an imaging study. We tested for interactions among all 4 of the predictors in the final model: proximal bowel dilation, symptomatic disease, duration of disease, and duration since last surgery. None of them was significant. A nomogram was developed to predict the 5-year surgery-free probability in patients undergoing EBD based on the above Cox regression model (Fig. 3). The predictions from the nomogram seemed to be accurate and discriminating, with a concordance index of 0.67, which was at its highest level when keeping all 4 of the variables reported in Table 2, including the nonsignificant variable of decreased duration of disease. The calibration curve showed that the prediction from our nomogram approximates the actual outcome. The nomogram was used by first locating the position on each predictor variable scale according to the predictor values. Each scale position had corresponding prognostic points (top axis). Point values for all of the predictor variables were determined consecutively and summed to arrive at a total point value. This value was then
CD patients with ICA stricture (N = 185)
Repeated dilations (N = 108)
One dilation (N = 77)
Surgery (N = 30, 40.0%) Mean surgery-free interval: 0.7 Indication for surgery
No surgery (N = 47) Mean follow-up: 1.8
Surgery (N = 36, 33.3%) Mean surgery-free interval: 2.5
EBD failure (n = 22)
EBD failure (n = 25)
Fistula/abscess (N = 6)
Fistula/abscess (n = 5)
EBD perforation (N = 2)
EBD perforation (n = 3)
Mean number of dilations: 3.6
No surgery (N = 72) Mean follow-up 4.7
Cancer (n = 1) Severe inflammation refractory to medical therapy (n = 2)
Figure 1. Outcomes after endoscopic through-the-scope balloon dilation (EBD) of ileocolic anastomosis (ICA) stricture attributed to recurrent Crohn’s disease (CD).
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DISCUSSION
Estimated probability of surgery, % 100
Our study aimed at identifying factors associated with the need for surgery after initial EBD for recurrent CD at a previously fashioned ICA to understand in which patients EBD had a potential for long-term success as opposed to earlier surgery. Our data confirm safety and feasibility of EBD for recurrent CD at ICA, echoing our previous institutional experience inclusive of both primary and secondary stricture in patients with CD.19 Our 1.1% per dilation perforation rate, corresponding with a 2.7% per-patient rate, favorably compares with the existing literature.10,16 EBD remains an attractive alternative to medical treatment in the management of ICA stricture for recurrent CD, which is frequently associated with limited benefit and may help in distinguishing inflammatory from fibrostenotic strictures.20 More importantly, our series provides novel information on risk factors associated with the need for surgery after initial EBD. We identified a longer interval from previous surgery and symptomatic disease as significant factors associated with the need for surgery, along with proximal bowel dilation in those patients for whom imaging was available. Type of anastomosis and endoscopic steroid injection were not associated with the need for subsequent surgery in our study. Reported risk factors associated with successful dilation include technical success during dilation,10,21,22 shorter
80
60
40
20
0
1
3
5
7
10
Time, years
Figure 2. Probability of surgery after endoscopic balloon dilation.
l ocated on the total point axis, from which a straight line was drawn down to determine the 5-year surgery-free probability. Points
Duration of Crohn’s disease (y)
0
50
10
45
40
20
35
30
30
25
40
20
15
50
10
60
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80
90
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Interval from last surgery (y) 0
Symptomatic disease
5
10
15
20
25
30
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40
45
180
200
Yes No Yes
Proximal ileal dilation No
Total Points 0
20
40
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80
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140
160
0.3
0.2
Predicted 5-year surgery-free probability 0.9
0.8
0.7
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0.1
Figure 3. Nomogram for the prediction of 5-year surgery-free probability among patients undergoing initial endoscopic balloon dilation. The nomogram is used by first locating the position on each predictor variable scale according to the predictor values. Each scale position has corresponding prognostic points (top axis). Point values for all of the predictor variables are determined consecutively and summed to arrive at a total point value, which is then located on the total point axis, from which a straight line is drawn down to determine the 5-year surgeryfree probability.
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Table 1. Univariable Cox proportional hazard model for risk factors associated with requirement of surgery after initial endoscopic dilation Variable Sex Women Men No. of previous operations 1 More than 1 Extraintestinal manifestations No Yes Smoking history Current smoker Former smoker Never smoker Passive smoker Symptomatic disease No Yes Medication use at time of EBD No Anti-inflammatory agents Biologics Immunomodulators Steroids Anastomotic technique End-to-end End-to-side Side-to-side Sedation General anesthesia Sedation Age, years Duration of Crohn’s disease, years Disease duration since latest operation, years Endoscopic balloon size, mm Rutgeerts score ≥1 0 Endoscopic steroid injection No Yes Endoscopic technical success After endoscopic dilation Before endoscopic dilation Technical failure Concurrent radiographic bowel stricture No Yes Radiographic proximal bowel dilation No Yes Radiographic bowel thickening No Yes Radiographic mucosal enhancement No Yes
Patient (n)
Salvage surgery, n (%)
Cox univariable HR (95% CI)
Cox univariable, p
85 100
36 (42) 30 (30)
– 0.76 (0.47–1.24)
0.27
117 68
32 (27) 34 (50)
– 1.94 (1.19–3.14)
0.006
150 35
54 (36) 12 (34)
– 0.90 (0.48–1.68)
0.74
35 46 100 4
14 (40) 18 (39) 33 (33) 1 (25)
– 0.65 (0.32–1.32) 0.60 (0.32–1.12) 0.53 (0.07–4.03)
??? 0.24 0.11 0.54
37 148
10 (27) 56 (38)
– 1.950 (0.992–3.833)
0.049
53 19 32 45 36
18 (34) 5 (26) 8 (25) 19 (42) 16 (44)
– 0.84 (0.31–2.27) 0.90 (0.39–2.08) 1.37 (0.72–2.63) 1.57 (0.80–3.11)
– 0.73 0.80 0.34 0.19
21 46 28
5 (24) 11 (24) 9 (32)
– 1.17 (0.39–3.51) 1.84 (0.59–5.80)
??? 0.77 0.30
23 162 185 185 185 180
8 (35) 58 (36) 66 (36) 66 (36) 66 (36) 64 (36)
– 0.67 (0.32–1.42) 0.992 (0.974–1.011) 0.99 (0.97–1.02) 1.015 (0.989–1.042) 0.97 (0.90–1.04)
0.29 0.41 0.61 0.27 0.35
111 74
34 (31) 32 (43)
– 1.20 (0.74–1.96)
0.45
150 35
53 (35) 13 (37)
– 0.82 (0.45–1.51)
0.52
156 12 17
53 (34) 3 (25) 10 (59)
– 1.03 (0.32–3.32) 2.51 (1.27–4.95)
– 0.96 0.008
161 24
52 (32) 14 (58)
– 2.20 (1.21–3.99)
0.008
87 42
31 (36) 26 (62)
– 2.12 (1.25–3.59)
0.005
24 96
8 (33) 45 (47)
– 1.32 (0.62–2.81)
0.47
36 84
14 (39) 39 (46)
– 1.03 (0.56–1.90)
0.93
Data were not available for all of the subjects. Balloon size was available for 180 patients, data on anastomotic technique on 95, data on radiographic bowel thickening on 120, and data on radiographic mucosal enhancement on 120. EBD = endoscopic balloon dilation.
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Table 2. Multivariable Cox proportional hazard model for risk factors associated with requirement of surgery after initial endoscopic dilation Variable Radiographic proximal bowel dilation No Yes Symptomatic disease No Yes Decreased duration of Crohn’s disease Increased Crohn’s disease duration since latest operation
Salvage surgery, n (%)
Cox multivariable HR (95% CI)
87 42
31 (36) 26 (62)
– 2.36 (1.38–4.03)
0.002
21 108 129 129
5 (24) 52 (48) 57 (44) 57 (44)
– 3.54 (1.41–8.93) 1.03 (0.99–1.06) 1.05 (1.01–1.10)
0.007
Patient (n)
length of stricture,10,17 nonulcerated stricture,18 and duration of CD.23 Some series have found that smoking was associated with the requirement of surgery.18 However, the data on smoking as an adverse prognosticator after EBD are controversial.18,24,25 Similarly, an increased C-reactive protein level has been inconsistently identified as a predictor for the need for intervention after index EBD.16,23 In addition, some series16 did not report any specific factor significantly associated with the need for new interventions after the index EBD, including medical therapy or active disease at the time of dilation. Our data did not include a C-reactive protein, which is not routinely used in our institution and has levels that can significantly fluctuate throughout the disease treatment. However, examination of a number of surgical and radiologic variables that have not been considered previously were included in this study, and we intentionally focused only on EBD for stricture at the ICA. We excluded, unlike most other studies,10,16,18 both de novo CD strictures and other disease locations14,26 so that sample heterogeneity could be minimized. We further constructed a nomogram using the above-mentioned variables that we believe can practically assist clinicians in counseling patients regarding their possibility of avoiding surgery for ICA stricture caused by recurrent CD. The present study and our previous study19 did not show significant association between the need for surgery and intralesional steroid injection. The injection was not found to reduce the time to redilation after EBD of Crohn’s ICA strictures; it had a trend toward a worse outcome in a previous pilot randomized, placebo-controlled trial.27,28 Of note, earlier studies suggest that infliximab was associated with stricture development.29–31 However, the direct link between the use of antitumor necrosis factor agents and stricture formation has been questioned.12,32–34 The assessment of pre-EBD imaging in the present study revealed that, in those who did have imaging data, a proximal bowel dilation was associated with a higher risk of subsequent surgery. In this regard, it is however important to point out that there might be a selection bias toward patients with more severe disease undergoing imaging evaluation which, unlike colonoscopy, is not a
Cox multivariable, p
0.12 0.028
routine follow-up study among patients who underwent ICA for CD. The other limitations of our study are related to its retrospective design. For example, the degree and the precise length of strictures could not be quantified in this study, and heterogeneity of patients’ characteristics remains inevitable. In particular, the clinical decision making on whether EBD or surgery was indicated for each individual patient was subjective and dependent on a variety of specific clinical circumstances. Future studies will be needed to assess the implications on long-term disease activity, quality of life, and reoperation rates of EBD when compared with upfront surgery for recurrent ICA stricture, which arguably might allow for a longer intervention-free survival by resecting rather than manipulating the anastomotic area of recurrence. In particular, although a subset of our patients did not require surgery for several years after EBD, we cannot reliably conclude that EBD saved them from an operation for CD without assessing a control group that was not treated with EBD for a comparable ICA stricture. CONCLUSION
EBD seems to be a safe and effective treatment modality. Patients with significant risk factors adversely affecting their nomogram scores should be counseled against EBD and recommended upfront surgery to treat recurrent CD. REFERENCES 1. De Cruz P, Kamm MA, Prideaux L, Allen PB, Desmond PV. Postoperative recurrent luminal Crohn’s disease: a systematic review. Inflamm Bowel Dis. 2012;18:758–777. 2. Lichtenstein GR, Hanauer SB, Sandborn WJ; Practice Parameters Committee of American College of Gastroenterology. Management of Crohn’s disease in adults. Am J Gastroenterol. 2009;104:464–484. 3. Rutgeerts P, Geboes K, Vantrappen G, et al. Natural history of recurrent Crohn’s disease at the ileocolic anastomosis after curative surgery. Gut. 1984;25:665–672.
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21. Scimeca D, Mocciaro F, Cottone M, et al. Efficacy and safety of endoscopic balloon dilation of symptomatic intestinal Crohn’s disease strictures. Dig Liver Dis. 2011;43:121–125. 22. Couckuyt H, Gevers AM, Coremans G, et al. Efficacy and safety of hydrostatic balloon dilation of ileocolic Crohn’s strictures: a prospective longterm analysis. Gut. 1995;36:577–580. 23. Bhalme M, Sarkar S, Lal S, Bodger K, Baker R, Willert RP. Endoscopic balloon dilation of Crohn’s disease strictures: results from a large United Kingdom series. Inflamm Bowel Dis. 2014;20:265–270. 24. Thomas-Gibson S, Brooker JC, Hayward CM, Shah SG, Williams CB, Saunders BP. Colonoscopic balloon dilation of Crohn’s strictures: a review of long-term outcomes. Eur J Gastroenterol Hepatol. 2003;15:485–488. 25. Gustavsson A, Magnuson A, Blomberg B, Andersson M, Halfvarson J, Tysk C. Smoking is a risk factor for recurrence of intestinal stricture after endoscopic dilation in Crohn’s disease. Aliment Pharmacol Ther. 2013;37:430–437. 26. Foster EN, Quiros JA, Prindiville TP. Long-term follow-up of the endoscopic treatment of strictures in pediatric and adult patients with inflammatory bowel disease. J Clin Gastroenterol. 2008;42:880–885. 27. Brooker JC, Beckett CG, Saunders BP, Benson MJ. Long-acting steroid injection after endoscopic dilation of anastomotic Crohn’s strictures may improve the outcome: a retrospective case series. Endoscopy. 2003;35:333–337. 28. East JE, Brooker JC, Rutter MD, Saunders BP. A pilot study of intrastricture steroid versus placebo injection after balloon dilation of Crohn’s strictures. Clin Gastroenterol Hepatol. 2007;5:1065–1069. 29. D’haens G, Van Deventer S, Van Hogezand R, et al. Endoscopic and histological healing with infliximab anti-tumor necrosis factor antibodies in Crohn’s disease: a European multicenter trial. Gastroenterology. 1999;116:1029–1034. 30. Vasilopoulos S, Kugathasan S, Saeian K, et al. Intestinal strictures complicating initially successful infliximab treatment for luminal Crohn’s disease. Am J Gastroenterol. 2000;95:2503. 31. Toy LS, Scherl EJ, Kornbluth A, et al. Complete bowel obstruction following initial response to infliximab therapy for Crohn’s disease: a series of a newly described complication. Gastroenterology. 2000;118:A569. 32. Lichtenstein GR, Olson A, Travers S, et al. Factors associated with the development of intestinal strictures or obstructions in patients with Crohn’s disease. Am J Gastroenterol. 2006;101:1030–1038. 33. Rieder F, Zimmermann EM, Remzi FH, Sandborn WJ. Crohn’s disease complicated by strictures: a systematic review. Gut. 2013;62:1072–1084. 34. Pallotta N, Barberani F, Hassan NA, Guagnozzi D, Vincoli G, Corazziari E. Effect of infliximab on small bowel stenoses in patients with Crohn’s disease. World J Gastroenterol. 2008;14:1885–1890.
Prediction of Need for Surgery After Endoscopic Balloon Dilation of Ileocolic Anastomotic Stricture in Patients With Crohn’s Disease Lei Lian, M.D., Ph.D.1,2 • Luca Stocchi, M.D.1 • Bo Shen, M.D.2 • Xiaobo Liu, M.S.3 Jessica Ma2 • Brook Zhang2 • Feza Remzi, M.D.1 1 Department of Colorectal Surgery, Cleveland Clinic, Cleveland, Ohio 2 Department of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, Ohio 3 Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland, Ohio
BACKGROUND: Endoscopic balloon dilation is used to treat ileocolic anastomotic stricture attributed to recurrent Crohn’s disease. OBJECTIVE: The purpose of this work was to investigate long-term outcomes after dilation of ileocolic anastomotic stricture and to identify risk factors associated with the need for subsequent surgical intervention. DESIGN: This was a retrospective study based on chart review of an electronic medical chart system. SETTINGS: The study was conducted at a tertiary care
center. PATIENTS: All of the eligible patients with ileocolic anastomotic stricture attributed to recurrent Crohn’s disease treated with endoscopic dilation between December 1998 and May 2013 were evaluated. Patients with concurrent enterocutaneous fistula or abdominal or pelvic abscess were excluded. MAIN OUTCOME MEASURES: The main outcome measure was the need for subsequent salvage surgery because of stricture-related symptoms. Funding/Support: Dr Stocchi was partially supported by the Story Garschina Endowed Chair.
RESULTS: A total of 185 patients with Crohn’s disease (45.9% women; mean age, 43.1 years; symptomatic strictures in 80%) underwent 462 endoscopic dilations of ileocolic anastomosis (median per-patient dilations, 2; range, 1–3). During a mean follow-up of 3.9 years, 27 patients (14.6%) required hospitalization without surgery for stricture-related symptoms, and 66 patients (35.7%) required subsequent salvage surgery. Specific medical management, type of anastomosis, and endoscopic intralesional steroid injection had no impact on the risk of needing surgery. Significant factors associated with the need for surgery on multivariable analysis were symptomatic disease (HR, 3.54 [95% CI, 1.41–8.93]), longer time interval from last surgery (HR, 1.05 [95% CI, 1.01–1.10]), and radiographic proximal bowel dilation (HR, 2.36 [95% CI, 1.38–4.03]). A nomogram estimating the need for surgery was created with a concordance index of 0.67. LIMITATIONS: The study was limited by its retrospective
design. CONCLUSIONS: Although endoscopic dilation is a valid option for ileocolic anastomotic stricture attributed to recurrent Crohn’s disease, the need for surgery is common. The nomogram can identify patients who might benefit from upfront surgery.
Financial Disclosure: None reported. Podium presentation at the meeting of The American Society of Colon and Rectal Surgeons, Hollywood, FL, May 17 to 21, 2014. Correspondence: Luca Stocchi, M.D., Desk A 30, Department of Colorectal Surgery, Cleveland Clinic, 9500 Euclid Ave, Cleveland, OH 44195. E-mail: [email protected] Dis Colon Rectum 2015; 58: 423–430 DOI: 10.1097/DCR.0000000000000322 © The ASCRS 2015 Diseases of the Colon & Rectum Volume 58: 4 (2015)
KEY WORDS: Anastomotic stricture; Crohn’s disease; Endoscopic balloon dilation; Nomogram; Prediction.
C
rohn’s disease (CD) is a chronic disease most commonly affecting the terminal ileum. It is estimated that ≤80% of patients with CD require surgical treatment at some point,1 most commonly ileocolic resection to treat CD-related strictures.2 However, the recurrence rate is high after ileocolic resection and may occur 423
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at the anastomotic site or in the neoterminal ileum.3,4 The cumulative probability of clinical recurrence is estimated at ≈10% per year.5 As recurrent disease progresses, anastomotic stricture may ensue and lead to bowel obstruction. The benefit of medical therapy in this setting is limited6 because of the mechanical nature of stricture, and surgical resection with reanastomosis is often required. Consequently, one fourth of the patients will require a second operation by 4 years, and approximately one-half by 10 to 15 years.7–9 Endoscopic through-the-scope balloon dilation (EBD) of the strictures has emerged as an effective alternative in patients with CD stricture,10 particularly for short and isolated strictures at the ileocolic anastomosis (ICA), which are often linear11 and may appear in the complete absence of disease recurrence.12 Although anastomotic strictures can be more technically challenging than de novo strictures,13 anastomotic strictures may also be associated with improved long-term outcomes when compared with de novo strictures.14 Currently, the majority of studies summarizing the outcomes of EBD of CD strictures have either a relatively small sample size with short follow-up or include both primary and secondary (anastomotic) strictures.10 Few studies have specifically focused on ICA.15 In addition, data pertaining to factors associated with long-term success as defined by the need for subsequent surgical resection after EBD for ICA stricture in patients with CD remain sparse.10,16–18 The aims of this study were, therefore, to analyze long-term outcomes after EBD for ICA stricture in patients with CD in a single institution and to identify variables observable at initial EBD that were risk factors for subsequent salvage surgery to treat ICA stricture attributed to recurrent CD.
PATIENTS AND METHODS Patients
The study was approved by the institutional review board at the Cleveland Clinic. A historical cohort of eligible patients with ICA stricture treated with EBD between December 1998 and May 2013 were evaluated. Inclusion Criteria and Exclusion Criteria
Patients were identified from an electronic health record (EHR; Epicsys, Verona, WI). Inclusion criteria for the study were patients seen in our IBD center and having a diagnosis of CD (International Classification of Diseases, Ninth Revision, Clinical Modification, code 555.9) documented on EHR and EBD in our billing database. This information was then confirmed by reviewing electronic charts. Clinical notes and endoscopy reports were reviewed to confirm EBD of ICA and to exclude patients with dilation of primary stricture. Patients with ileorectal anastomosis were excluded.
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Demographic and Clinical Variables
Demographics (age, sex, and race) were extracted from the EHR. Clinical, endoscopic, histologic, and radiographic data were collected by chart review. Collected data included age at diagnosis, age at the time of treatment, duration of CD (time interval between diagnosis of CD and EBD of ICA stricture), symptoms, smoking history (never, current, or ex-smoker), presence of extraintestinal manifestations, and date of most-recent follow-up. CD medications within the 3 months before EBD were categorized into 5-aminosalicylates, immunomodulators, steroids (oral or intravenous corticosteroids), or biologics. Escalation of medical therapy was defined as use of increased dosage of the same drug or use of a higher class of CD medication after EBD as compared with that before EBD. Endoscopy reports were reviewed to extract data on stricture length, presence and location of concurrent stricture, balloon size, use of intralesional steroid injection, and immediate complications (major bleeding, perforation, or death). Imaging reports within the 3 months preceding EBD (CT, CT enterography, magnetic resonance enterography, or barium studies) were reviewed to determine stricture length and the presence of proximal bowel dilation. Concurrent stricture was defined as the presence of additional stricture(s) other than the ICA stricture located elsewhere in the ileum, jejunum, or colon. Indications and Technique of Endoscopic Balloon Dilation
The decision to perform EBD generally followed the diagnosis of ICA stricture based on clinical presentation and imaging studies. However, EBD could also be performed on ICA strictures that were incidentally encountered in the course of a routine surveillance colonoscopy at the discretion of the endoscopist. Anastomotic or preanastomotic strictures >4 cm and known fistulizing abdominal CD were considered to be not amenable to EBD or as contraindications to EBD in our practice. The procedure was typically done by IBD specialists or therapeutic endoscopists at our institution. Once the stricture was endoscopically visualized, the through-the-scope controlled radial expansion dilating balloon was passed through the biopsy channel through the stricture. The balloon diameter ranged between 12 and 20 mm. Once in place, the balloon was inflated with water using a stepwise approach. The pressure was monitored closely by the assistant throughout the procedure. The pressure was maintained for a few seconds, and then the balloon was deflated. The process could be repeated several times during the same procedure until an adequate visualization of the lumen was achieved unless an angulation or narrow stricture prohibited the passage of the colonoscope. Specific balloon size and endoscopic dilation technique were left at the discretion of the individual endoscopist.
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Outcome Measurements Primary outcome was the need for salvage surgery to treat the ICA stricture because of recurrent CD. Other outcomes, including immediate technical failure, repeated dilation, stricture-associated emergency department visit, hospitalization, and escalation of medical therapy to immunomodulators/biologics were also examined. Major complications were defined as perforation, excessive bleeding requiring transfusion, and death. Technical failure was defined as an inability to pass the endoscope through the anastomosis after dilation. Patient follow-up started from the date of the first EBD until the date of the primary outcome or censoring at the date of the most recent contact. Patients and/or treating physicians were contacted via telephone if no follow-up data were retrievable from our medical charts. Statistical Analysis
Descriptive statistics included means and SDs or medians and interquartile ranges for continuous variables and frequencies and percentages for categorical variables. Univariable analysis was performed using the χ2 and Fisher exact tests (if expected cell counts were less than 5) for categorical study variables, and Student t tests and Wilcoxon ranksum tests were used for continuous variables. Kaplan-Meier analysis was used to calculate the long-term risk of surgical resection to treat ICA strictures. The multivariable Cox proportional hazards model using backward variable selection (ie, step-down method) was used to identify risk factors identifiable at the time of the initial EBD associated with the requirement of surgery adjusting for confounding factors. A number of different combinations among the examined variables were tested for possible interactions, in particular among the independent factors associated with the need for salvage surgery in the final multivariable model. Restricted cubic splines were used for continuous variables to take care of possible nonlinearity of continuous predictors. The nonlinearity terms were removed from the model when shown to be unnecessary. Differences were considered to be statistically significant when a p value was 0) on initial EBD, technique used in the construction of the ICA, and endoscopic steroid injection had no relationship with the risk of having surgery (Table 1). Subgroup Analysis of Patients With Available Imaging Data
Radiographic examination within 3 months before initial EBD was performed in 129 patients, including CT (n = 98), magnetic resonance (n = 12), small-bowel series (n = 16), and abdominal plain film (n = 3). The evaluation of possible associations between radiographic features and the need for subsequent surgery is also included in Table 1. In a subgroup analysis, patients with bowel
dilation proximal to ICA stricture and concurrent bowel stricture elsewhere had a significantly increased risk of requiring salvage surgery. Multivariable Cox Regression Model for Risk of Subsequent Surgery and Development of a Nomogram
A Cox regression model was performed to assess the risk factor for subsequent surgery (Table 2). Significant factors associated with the requirement of surgery on multivariable analysis were symptomatic disease, longer interval from last surgery, and presence of proximal bowel dilation on an imaging study. We tested for interactions among all 4 of the predictors in the final model: proximal bowel dilation, symptomatic disease, duration of disease, and duration since last surgery. None of them was significant. A nomogram was developed to predict the 5-year surgery-free probability in patients undergoing EBD based on the above Cox regression model (Fig. 3). The predictions from the nomogram seemed to be accurate and discriminating, with a concordance index of 0.67, which was at its highest level when keeping all 4 of the variables reported in Table 2, including the nonsignificant variable of decreased duration of disease. The calibration curve showed that the prediction from our nomogram approximates the actual outcome. The nomogram was used by first locating the position on each predictor variable scale according to the predictor values. Each scale position had corresponding prognostic points (top axis). Point values for all of the predictor variables were determined consecutively and summed to arrive at a total point value. This value was then
CD patients with ICA stricture (N = 185)
Repeated dilations (N = 108)
One dilation (N = 77)
Surgery (N = 30, 40.0%) Mean surgery-free interval: 0.7 Indication for surgery
No surgery (N = 47) Mean follow-up: 1.8
Surgery (N = 36, 33.3%) Mean surgery-free interval: 2.5
EBD failure (n = 22)
EBD failure (n = 25)
Fistula/abscess (N = 6)
Fistula/abscess (n = 5)
EBD perforation (N = 2)
EBD perforation (n = 3)
Mean number of dilations: 3.6
No surgery (N = 72) Mean follow-up 4.7
Cancer (n = 1) Severe inflammation refractory to medical therapy (n = 2)
Figure 1. Outcomes after endoscopic through-the-scope balloon dilation (EBD) of ileocolic anastomosis (ICA) stricture attributed to recurrent Crohn’s disease (CD).
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DISCUSSION
Estimated probability of surgery, % 100
Our study aimed at identifying factors associated with the need for surgery after initial EBD for recurrent CD at a previously fashioned ICA to understand in which patients EBD had a potential for long-term success as opposed to earlier surgery. Our data confirm safety and feasibility of EBD for recurrent CD at ICA, echoing our previous institutional experience inclusive of both primary and secondary stricture in patients with CD.19 Our 1.1% per dilation perforation rate, corresponding with a 2.7% per-patient rate, favorably compares with the existing literature.10,16 EBD remains an attractive alternative to medical treatment in the management of ICA stricture for recurrent CD, which is frequently associated with limited benefit and may help in distinguishing inflammatory from fibrostenotic strictures.20 More importantly, our series provides novel information on risk factors associated with the need for surgery after initial EBD. We identified a longer interval from previous surgery and symptomatic disease as significant factors associated with the need for surgery, along with proximal bowel dilation in those patients for whom imaging was available. Type of anastomosis and endoscopic steroid injection were not associated with the need for subsequent surgery in our study. Reported risk factors associated with successful dilation include technical success during dilation,10,21,22 shorter
80
60
40
20
0
1
3
5
7
10
Time, years
Figure 2. Probability of surgery after endoscopic balloon dilation.
l ocated on the total point axis, from which a straight line was drawn down to determine the 5-year surgery-free probability. Points
Duration of Crohn’s disease (y)
0
50
10
45
40
20
35
30
30
25
40
20
15
50
10
60
5
70
80
90
100
0
Interval from last surgery (y) 0
Symptomatic disease
5
10
15
20
25
30
35
40
45
180
200
Yes No Yes
Proximal ileal dilation No
Total Points 0
20
40
60
80
100
120
140
160
0.3
0.2
Predicted 5-year surgery-free probability 0.9
0.8
0.7
0.6
0.5
0.4
0.1
Figure 3. Nomogram for the prediction of 5-year surgery-free probability among patients undergoing initial endoscopic balloon dilation. The nomogram is used by first locating the position on each predictor variable scale according to the predictor values. Each scale position has corresponding prognostic points (top axis). Point values for all of the predictor variables are determined consecutively and summed to arrive at a total point value, which is then located on the total point axis, from which a straight line is drawn down to determine the 5-year surgeryfree probability.
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Table 1. Univariable Cox proportional hazard model for risk factors associated with requirement of surgery after initial endoscopic dilation Variable Sex Women Men No. of previous operations 1 More than 1 Extraintestinal manifestations No Yes Smoking history Current smoker Former smoker Never smoker Passive smoker Symptomatic disease No Yes Medication use at time of EBD No Anti-inflammatory agents Biologics Immunomodulators Steroids Anastomotic technique End-to-end End-to-side Side-to-side Sedation General anesthesia Sedation Age, years Duration of Crohn’s disease, years Disease duration since latest operation, years Endoscopic balloon size, mm Rutgeerts score ≥1 0 Endoscopic steroid injection No Yes Endoscopic technical success After endoscopic dilation Before endoscopic dilation Technical failure Concurrent radiographic bowel stricture No Yes Radiographic proximal bowel dilation No Yes Radiographic bowel thickening No Yes Radiographic mucosal enhancement No Yes
Patient (n)
Salvage surgery, n (%)
Cox univariable HR (95% CI)
Cox univariable, p
85 100
36 (42) 30 (30)
– 0.76 (0.47–1.24)
0.27
117 68
32 (27) 34 (50)
– 1.94 (1.19–3.14)
0.006
150 35
54 (36) 12 (34)
– 0.90 (0.48–1.68)
0.74
35 46 100 4
14 (40) 18 (39) 33 (33) 1 (25)
– 0.65 (0.32–1.32) 0.60 (0.32–1.12) 0.53 (0.07–4.03)
??? 0.24 0.11 0.54
37 148
10 (27) 56 (38)
– 1.950 (0.992–3.833)
0.049
53 19 32 45 36
18 (34) 5 (26) 8 (25) 19 (42) 16 (44)
– 0.84 (0.31–2.27) 0.90 (0.39–2.08) 1.37 (0.72–2.63) 1.57 (0.80–3.11)
– 0.73 0.80 0.34 0.19
21 46 28
5 (24) 11 (24) 9 (32)
– 1.17 (0.39–3.51) 1.84 (0.59–5.80)
??? 0.77 0.30
23 162 185 185 185 180
8 (35) 58 (36) 66 (36) 66 (36) 66 (36) 64 (36)
– 0.67 (0.32–1.42) 0.992 (0.974–1.011) 0.99 (0.97–1.02) 1.015 (0.989–1.042) 0.97 (0.90–1.04)
0.29 0.41 0.61 0.27 0.35
111 74
34 (31) 32 (43)
– 1.20 (0.74–1.96)
0.45
150 35
53 (35) 13 (37)
– 0.82 (0.45–1.51)
0.52
156 12 17
53 (34) 3 (25) 10 (59)
– 1.03 (0.32–3.32) 2.51 (1.27–4.95)
– 0.96 0.008
161 24
52 (32) 14 (58)
– 2.20 (1.21–3.99)
0.008
87 42
31 (36) 26 (62)
– 2.12 (1.25–3.59)
0.005
24 96
8 (33) 45 (47)
– 1.32 (0.62–2.81)
0.47
36 84
14 (39) 39 (46)
– 1.03 (0.56–1.90)
0.93
Data were not available for all of the subjects. Balloon size was available for 180 patients, data on anastomotic technique on 95, data on radiographic bowel thickening on 120, and data on radiographic mucosal enhancement on 120. EBD = endoscopic balloon dilation.
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Table 2. Multivariable Cox proportional hazard model for risk factors associated with requirement of surgery after initial endoscopic dilation Variable Radiographic proximal bowel dilation No Yes Symptomatic disease No Yes Decreased duration of Crohn’s disease Increased Crohn’s disease duration since latest operation
Salvage surgery, n (%)
Cox multivariable HR (95% CI)
87 42
31 (36) 26 (62)
– 2.36 (1.38–4.03)
0.002
21 108 129 129
5 (24) 52 (48) 57 (44) 57 (44)
– 3.54 (1.41–8.93) 1.03 (0.99–1.06) 1.05 (1.01–1.10)
0.007
Patient (n)
length of stricture,10,17 nonulcerated stricture,18 and duration of CD.23 Some series have found that smoking was associated with the requirement of surgery.18 However, the data on smoking as an adverse prognosticator after EBD are controversial.18,24,25 Similarly, an increased C-reactive protein level has been inconsistently identified as a predictor for the need for intervention after index EBD.16,23 In addition, some series16 did not report any specific factor significantly associated with the need for new interventions after the index EBD, including medical therapy or active disease at the time of dilation. Our data did not include a C-reactive protein, which is not routinely used in our institution and has levels that can significantly fluctuate throughout the disease treatment. However, examination of a number of surgical and radiologic variables that have not been considered previously were included in this study, and we intentionally focused only on EBD for stricture at the ICA. We excluded, unlike most other studies,10,16,18 both de novo CD strictures and other disease locations14,26 so that sample heterogeneity could be minimized. We further constructed a nomogram using the above-mentioned variables that we believe can practically assist clinicians in counseling patients regarding their possibility of avoiding surgery for ICA stricture caused by recurrent CD. The present study and our previous study19 did not show significant association between the need for surgery and intralesional steroid injection. The injection was not found to reduce the time to redilation after EBD of Crohn’s ICA strictures; it had a trend toward a worse outcome in a previous pilot randomized, placebo-controlled trial.27,28 Of note, earlier studies suggest that infliximab was associated with stricture development.29–31 However, the direct link between the use of antitumor necrosis factor agents and stricture formation has been questioned.12,32–34 The assessment of pre-EBD imaging in the present study revealed that, in those who did have imaging data, a proximal bowel dilation was associated with a higher risk of subsequent surgery. In this regard, it is however important to point out that there might be a selection bias toward patients with more severe disease undergoing imaging evaluation which, unlike colonoscopy, is not a
Cox multivariable, p
0.12 0.028
routine follow-up study among patients who underwent ICA for CD. The other limitations of our study are related to its retrospective design. For example, the degree and the precise length of strictures could not be quantified in this study, and heterogeneity of patients’ characteristics remains inevitable. In particular, the clinical decision making on whether EBD or surgery was indicated for each individual patient was subjective and dependent on a variety of specific clinical circumstances. Future studies will be needed to assess the implications on long-term disease activity, quality of life, and reoperation rates of EBD when compared with upfront surgery for recurrent ICA stricture, which arguably might allow for a longer intervention-free survival by resecting rather than manipulating the anastomotic area of recurrence. In particular, although a subset of our patients did not require surgery for several years after EBD, we cannot reliably conclude that EBD saved them from an operation for CD without assessing a control group that was not treated with EBD for a comparable ICA stricture. CONCLUSION
EBD seems to be a safe and effective treatment modality. Patients with significant risk factors adversely affecting their nomogram scores should be counseled against EBD and recommended upfront surgery to treat recurrent CD. REFERENCES 1. De Cruz P, Kamm MA, Prideaux L, Allen PB, Desmond PV. Postoperative recurrent luminal Crohn’s disease: a systematic review. Inflamm Bowel Dis. 2012;18:758–777. 2. Lichtenstein GR, Hanauer SB, Sandborn WJ; Practice Parameters Committee of American College of Gastroenterology. Management of Crohn’s disease in adults. Am J Gastroenterol. 2009;104:464–484. 3. Rutgeerts P, Geboes K, Vantrappen G, et al. Natural history of recurrent Crohn’s disease at the ileocolic anastomosis after curative surgery. Gut. 1984;25:665–672.
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