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Decision-making in ileocecal Crohn’s disease management: surgery versus pharmacothera
http://gidiv.ucsf.edu/course/things/Eshuis.pdf
Decision-making in ileocecal Crohn’s disease management: surgery versus
pharmacotherapy
Expert Rev. Gastroenterol. Hepatol. 4(2), 181–189 (2010)
Emma J Eshuis,
Pieter CF Stokkers and
Willem A Bemelman†
†Author for correspondence Department of Surgery, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands Tel.: +31 205 669 111
Fax: +31 205 669 285 [email protected]
Ileocecal Crohn’s disease (CD) can be treated medically as well as surgically. Both treatment modalities have been improved markedly in the last two decades, making CD more manageable. However, multidisciplinary research, addressing issues such as timing of surgery or medical treatment versus surgery, is scarce. Particularly in limited ileocecal CD, ileocolic resection might be a good alternative to long-term medical therapy. This review discusses the evidence on medical and surgical treatment options for ileocecal CD. It provides an aid in decision-making by discussing a treatment algorithm that can be used until further evidence on treatment is available.

Crohn’s disease (CD) is a chronic inflammatory bowel disorder that can affect the entire GI tract. In 25–30% of cases, disease activity is confined to the terminal ileum with or without cecal involvement [1]. Until 10–15 years ago, options in treating ileocecal CD were limited. Treatment focussed on symptom control rather than achieving long-term remission [2]. The medical treatment options consisted of 5-aminosalycitates (5-ASA), antibiotics and steroids. At that time, immune suppressors, such as meth- otrexate (MTX) or azathioprine (AZA), were already available. However, efficacy was not yet established and these therapies were rarely applied because of concerns of side effects [3]. In general, treatment consisted of a course of steroids for remission induction and 5-ASA compounds as maintenance therapy. Once refractory to steroids, patients were referred to the surgeon for ileocolic resection. Recurrent disease could lead to multiple resections with the inherent risk of complications requiring a deviating stoma and development of a short bowel syndrome. As a consequence, gastroenterologists were reluctant to send their patients to the surgeon and patients were chronically or repetitively treated with steroids. Surgery was considered to be the last option offered to patients with steroid-refractory disease.
In the last two decades treatment algorithms have changed. Evidence on the efficacy of immune suppressors has accumulated, proving to be efficient in maintaining remission in the majority of patients. Trials on 5-ASA showed that 5-ASA effectiveness is limited [4]. However, the most important development has been the discovery of biological anti-TNF therapy. Uncovering the important role of the proinflammatory cytokine TNF-a in the immune response has led to the development of monoclonal antibodies targeting this cytokine. These compounds appeared to be highly efficacious in the treatment of CD. Infliximab (IFX; 1998) and adalimumab (ADA; 2007) are registered treatments for moderate-to-severe CD and, in the USA, certolizumab pegol (2008) was added to the list [5,6].
During this time the surgical management of CD was also improving. Minimal invasive surgery, bowel sparing techniques and enhanced recovery programs after surgery have greatly improved the quality of surgery and the peri- operative management resulting in earlier recovery, less morbidity and superior long-term results. Particularly in limited localized ileocecal disease activity, surgery is an effective treatment strategy with a quick restoration of quality of life (QoL).

In tertiary referral centers for inflammatory bowel disease (IBD) patients are often seen in joint clinics and decision-making is often performed in multidisciplinary teams. However, little research has been undertaken on issues concerning the surgical and medical treatment in terms of efficacy, costs and QoL. The available literature consists of a few opinion papers concerning timing of surgery in the era of biological therapies [7–9] and guidelines [10–12] lacking definitive answers.
The aim of this review is to discuss the medical and surgical treatment options for ileocecal CD and to provide an aid in decision making by discussing a treatment algorithm that can be used until further evidence on the treatment is available.
Ileocecal CD
When Burril Crohn first reported the disease that we now know as CD, he described a regional ileitis [13]. In 25–30% of CD patients, the ileocecal junction is the only region where the disease is active [14].
Typical complaints of patients with active CD in the ileocecal region are abdominal pain in the lower right quadrant, persistent diarrhea, fever with or without anorexia, nausea and vomiting as signs of obstruction [15]. The stenosis is caused by a combination of irreversible fibrosis due to repetitive relapses and/or edema caused by inflammation.
Medical options
The most commonly applied treatment algorithm in the medi- cal management of CD is a step-up approach. In this approach, therapy is started with the least toxic agents first. If not sufficiently effective, more potent drugs will be added or started instead. Some gastroenterologists propose a more aggressive approach, arguing that with the step-up approach, agents with low efficacy are used for prolonged periods of time, while uncontrolled inflammation continues, resulting in tissue damage. The newly advocated approach is a top-down strategy with initially aggressive treatment with biologic therapy and early immune suppression [16]. Decision-making in top-down versus step-up strategies was recently addressed in a previous issue of this journal and is beyond the scope of this review [17,18].
The American and European guidelines agree that for drug induced remission, patients with mild ileal CD are best treated with budesonide [10–12]. Budesonide is an ethylcellulose-coated steroid that is released in the ileum. Owing to the low systematic bioavailability as a result of the high first pass metabolism (90%), budesonide optimizes the advantages of steroid therapy and at the same time minimizes the risk of systemic side effects [19]. In the Cochrane review by Seow et al. budesonide proved to be more effective than placebo or mesalamine for induction of remission in CD [20]. Although less effective when compared with conventional steroids, budesonide was associated with a lower rate of adverse events.
For patients with a moderate-to-severe flare of disease, oral steroids (prednisone) are indicated [10–12]. In patients who require steroids to induce remission, concomitant maintenance therapy consisting of AZA or 6-mercaptopurine (6MP) must be considered, or MTX in the case of intolerance to thiopurines [10–12]. 6MP and its prodrug AZA are efficient for induction of remission, but have a delayed onset of action. However, when started together with a steroid remission induction course, AZA has been shown to be effective as maintenance therapy once the steroids were tapered [21,22]. MTX was shown to be significantly more effective compared with placebo in inducing and maintaining remission (remission induction: MTX 39% vs placebo 19% [p = 0.025]; maintenance of remission: MTX 65% vs placebo 14% [p = 0.04]) [23,24]. In current treatment strategies it is mainly applied as maintenance therapy.
Patients having recurrent flares despite immunomodulating maintenance therapy or showing intolerance necessitating repetitive steroid courses, require an anti-TNF agent as the next step in the medical treatment algorithm [10–12]. The first biological anti-TNF agent registered for the treatment of CD was IFX. In the USA it was approved by the US FDA in 1998, followed by approval in Europe in 1999. IFX is a chimeric human–murine antibody binding membrane bound as well as free soluble TNF, thereby neutralizing proinflammatory and regulatory actions of TNF. Multiple trials have established IFX for remission induction and maintenance therapy [25–27]. In 2007, the fully human anti-TNF agent ADA was added to the biological drug armamentarium, showing similar results in inducing and maintaining remission in ileocolonic CD [28–30].
Both IFX and ADA have shown clear efficacy in inducing remission (responses 65 and 58% in the large IFX trials [25,27]; 59% response at week 4 of the large ADA trial [28]). However, after 1 year only 40–50% of responding patients still experience benefits from these agents, as a large proportion of patients will lose response to these drugs [31,32]. In patients who became intolerant to IFX or who lost response, the Gauging Adalimumab Efficacy in Infliximab Nonresponders (GAIN) trial, a double-blind randomized trial, showed that ADA was significantly more efficient compared with placebo in restornig remission [33]. However, the gain was limited: after 4 weeks, remission was achieved in only 21% of patients (34 out of 159) in the ADA group versus 7% in the placebo group.
Safety of medical therapy
The long-term safety of medical therapy for CD remains to be determined. Since most medical therapies in CD are immune-suppressive there is a risk of developing opportunistic infections. In a large case control study, the use of corticosteroids, AZA/6MP and IFX was shown to be associated significantly with the development of opportunistic infections in IBD patients, especially when the compounds are used in combination [34]. A large cohort study recently showed that thiopurine use (AZA or 6MP) for IBD was associated with an increased risk of developing lymphoproliferative disorders (multivariate adjusted HR between patients receiving thiopurines and those who never received thiopurines: 5.28 [95% CI: 2.01–13.9]) [35]. A debate on the combined therapy of immuno- modulating agents, such as AZA or 6MP, and anti-TNF therapy is ongoing [36–38]. On one hand, concomitant immunomodulating therapy was shown to suppress the chance of developing antibodies against IFX, thereby preserving efficacy of IFX [39] and resulting in higher response rates [40]. On the other hand, emerging reports on hepatocellular T-cell lymphoma in young CD patients on anti-TNF in combination with thiopurines have made gastroenterologists reluctant to combine immune suppression for longer periods [41]. A study claiming equivalent efficacy of maintenance for IFX mono therapy and combined immune suppression is flawed by lack of power [42]. Other studies addressing the issue of tapering combined immune suppression are currently being undertaken [43,101].
QoL in medical treatment
Bernklev et al. found in a large cohort study that patients with CD have a significantly reduced QoL owing to frequent relapses, repetitive steroid courses, side effects of immunomodulating therapy or extra intestinal manifestations [44]. Feagan et al. investigated the QoL of patients receiving IFX remission induction and maintenance therapy for up to 1 year in the patients participating in A Crohn’s Disease Clinical Trial Evaluating Infliximab in a New Long-
Term Treatment Regimen (ACCENT) I Trial [45]. In this double-blind randomised trial, patients received IFX remission induction and maintenance therapy. The authors concluded that IFX therapy significantly improved QoL compared with the QoL in responders before therapy. This QoL remained statistically improved in those patients receiving IFX maintenance therapy compared with placebo receivers. A similar study has been performed for ADA (Crohn’s Trial of the Fully Human Antibody Adalimumab for Remission Maintenance [CHARM] trial), with similar conclusions [46]. However, no QoL data exist for patients on maintenance therapy with IFX or ADA compared with healthy controls. It might be hypothesized that the impaired QoL in patients with long-lasting immunomodulating therapy also applies for patients on long-term biological therapy. Moreover, data on QoL in patients on anti-TNF therapy for more than 1 year are scarce. Casellas et al. measured QoL in CD patients for up to 4 years after the start of IFX maintenance therapy [47]. However, QoL was only measured in those patients who remained in remission. The majority of patients relapsed and had a decline in quality of life but were excluded from the study, leaving the data unsuitable for interpretation.
Costs
Up to the point that biologicals are prescribed, costs for maintenance therapy remain low. However, a significant number of patients will require further treatment after failed steroid and immunomodulating therapy. Currently, gastroenterologists generally prescribe biological therapy.
In The Netherlands biological therapy is expensive; 100 mg of IFX costs €570. This implies that costs for a patient with a weight of 75 kg who starts IFX remission induction and maintenance therapy will accumulate to a total sum of €17,000 in 1 year, apart from costs for daycare at the hospital, estimated at €500 per infusion. Likewise, 40 mg of ADA costs €1065 in The Netherlands; 1 year of therapy (one injection of 80 mg followed by 40 mg every 2 weeks) totals €28751.49 (Figure 1).
Bodger et al. performed a Markov analysis to assess the cost–effectiveness of biological therapy. They concluded that in responders, compared with standard therapy, both IFX and ADA may represent a cost effective use of healthcare resources for up to 4 years, since costs fell below the £30,000 per quality- adjusted life years threshold for cost–effectiveness in the UK [48]. The Canadian Agency for Drugs and Technologies in Health, however, has published a cost effectiveness analysis regarding anti-TNF drugs for the treatment of refractory IBD, comparing them with surgery and with conventional treatments [102]. The conclusion was that costs associated with anti-TNF treatments are high and that anti-TNF treatment might not be cost effective. Since anti-TNF treatment might not be cost effective, it must be used selectively. Other alternatives, such as surgery become more important. A real-life comparison of anti-TNF and surgery for ileocecal CD disease in terms of costs and quality-adjusted life years is needed.
Surgical options
The surgical treatment of ileocecal CD consists of an ileocolic resection. During the past few decades, surgical research has been focussing on the comparison of laparoscopic and open surgery. These studies provided evidence on short and long-term results of both approaches. Short-term studies showed that QoL is quickly restored after the ileocolic resection. Long-term studies revealed a low recurrence rate, indicating that ileocolic resection is a very effective treatment for localized ileocecal CD.
Short-term outcomes after ileocolic resection
Four systematic reviews describing the short-term results after a laparoscopic versus open ileocolic resection have been published. These reviews were based on 12–16 studies including two randomized trials [49,50]. Polle et al. reported a postoperative surgical reintervention rate of 0–8.3% in the different studies analyzed in their review (Table 1) [51]. Overall morbidity was 15.3% (Table 2). One might hypothesize that these results were achieved in specialized institutions, thereby not reflecting daily practice. A nationwide analysis of all ileocolic resections performed in France in the period 2000–2004 showed a similar overall morbidity rate of 15% in 49,609 procedures [52]. In-hospital mortality in this cohort was 0.9% and was significantly higher after an open approach (0.9% in open operated patients compared with 0.2% after laparoscopic resection; p ≤ 0.01).
Several studies have investigated the risk of postoperative complications in the setting of prior anti-TNF therapy. A systematic review published in 2006 concluded that there was no increased rate of postoperative complications associated with immuno-modulator use [53]. More publications have appeared since then, but these studies have shown conflicting results [54,55]. It is, there- fore, as yet unknown whether anti-TNF or immunomodulator therapy should be avoided in the preoperative setting. Maartense et al. measured QoL before and during the 3 months after the initial resection [49]. Patients had a quick restoration of QoL after surgery: a short deterioration was resolved after 2 weeks, and after 3 months QoL had increased significantly (p < 0.0001 compared with the baseline measurement). With regard to the comparison of laparoscopy and open surgery, all reviewers concluded that laparoscopy had short-term benefits over open surgery.
Long-term results
Long-term follow-up data of ileocolic resection also originate from trials that compared the laparoscopic and open techniques. The two most recent long-term studies are follow-up studies from two randomized trials [56,57]. In a cohort of 56 patients with a median follow-up of 10.5 years, Stocchi et al. found an overall recurrence rate of 52% [56]. However, the recurrence rate requiring re-resection was 28.5%, and only an additional 9% of patients required a readmission to treat the disease medically. This means that half of patients remained disease free until 10 years after the resection. Of the other half of patients, one third of patients could be managed in an out-patient setting.
Our own data showed an overall clinical recurrence rate of 38% with only five out of 55 patients (9%) requiring re-resection [57]. Median follow-up in this study was 6.8 years. Long-term QoL in this study was comparable to the QoL of healthy controls on most subscales subscribing the efficacy of laparoscopic ileocolic resection. Important features of laparoscopic surgery were a superior cosmesis and fewer incisional hernias.
Costs
In the study of Maartense et al., median overall costs were significantly lower after a laparoscopic approach compared with the open technique (Figure 1) [49]. The median costs, including relaparotomies, hospital stay and readmission costs, were €6.412 for the laparoscopic procedure and €8.196 for the open approach. Young-Fadok et al. calculated similar costs [58]. After a follow-up of 6.8–10.5 years, no additional costs were made apart from the periodical out-patient visits in 50–60% of patients. The remaining patients had extra costs as result of a relapse requiring medical or surgical treatment.
Early versus late surgery
Aratari et al. retrospectively compared outcomes of patients who underwent surgery at time of diagnosis with those of patients who had surgery during the course of the disease [59]. They concluded that the incidence of clinical recurrence requiring immuno-suppressive therapy was significantly lower in the early-surgery group, indicating that early surgery might lead to a prolonged clinical remission. Owing to the retrospective, nonrandomized design of the trial, the comment on this study is that the two groups were not comparable: in the early-surgery group, the surgery was often performed because of clinical need, and not to investigate a top-down approach, while the late surgery patients had more severe disease activity associated with a shorter disease-free survival [60].
From a patient perspective, an older but interesting study is that of Scott and Hughes from 1994 [61]. A total of 80 patients who underwent an ileocolic resection were questioned if they would - in retrospect - have preferred an earlier or later resection, or at the same time as it was done. Of the 70 recipients, 74% answered that they would have wanted an earlier resection, and not one patient would have preferred their operation to have been later.
Since this study lacks a control group it is a biased study. It is, however, the only evidence available about the patients’ opinion on timing of surgery and, therefore, worth mentioning.
In summary, the major short-term benefit of an ileocolic resection is the quick restoration in QoL due to the removal of the diseased bowel segment at the expense of a (small) risk of severe complications. When looking at the long-term follow-up a low recurrence rate requiring re-resection was found, but the overall relapse rate was also relatively low.
Expert commentary: medication or surgery?
The treatment success of IFX in therapy-resistant CD is evident and surgical resection is commonly appreciated as a negative outcome in the treatment of CD. As a consequence, surgical resection as a treatment option is often overlooked and patients are frequently unnecessarily treated with consecutive courses of immunosuppressant with a significant burden on the QoL. Isolated ileocecal CD in particular offers the alternative of surgical resection and may have gains in cost–effectiveness and QoL that extend far beyond the benefits of medical therapy.
Both the medical and surgical strategy can be advocated on clinical arguments. On one hand, medical treatment can prolong resection-free survival, thereby preventing the risks of surgery; on the other hand, studies have shown that resection often leads to a quick restoration of QoL with a low long-term recurrence rate. Moreover, long-term results of laparoscopic ileocolic resection are well established now, while, by contrast, little is known about the efficacy and QoL of long-term immunomodulating therapy and treatment with biologicals.
Guidelines differ in their recommendations. The European guidelines state that for severely active localized ileocecal disease not responding to conventional therapy, “infliximab should be considered ... although surgical options should also be considered and discussed” [10]. The American College of Gastroenterology practice guideline states that surgery is advocated for “neoplastic/preneoplastic lesions, obstructing stenoses, suppurative complications, or medically intractable disease”, suggesting that all medical options should have been tried before turning to surgery [11]. It is, however, noted that with the better postoperative maintenance schemes and appropriate surgery, the prolongation of ineffective medical management is no longer justified to ‘avoid’ surgery.
In the decision of whether to treat surgically or medically, it is important to take several factors into consideration that preclude one of the treatment options beforehand (see algorithm, Figure 2). First, it is important to rule out disease activity elsewhere, because in these cases, an ileocolic resection will not suffice. In case of severe extraintestinal manifestations or autoimmune comorbidity, medical therapy is indicated to treat both disease entities. Patients with active perianal fistulas concomitant with ileocecal CD are best treated with anti-TNF. On the contrary, however, patients with obstructive symptoms due to a fibrotic terminal ileum are best treated surgically, since medication will have no effect. In clinical practice the distinction between a fibrotic stricture and inflammatory stenosis may be difficult. Prestenotic dilatation and absence of wall thickening and an inflammatory infiltrate on MRI indicate a predominant fibrotic component, whereas ulceration and edema of the mucosa and the bowel wall point towards an inflammatory stenosis. Frequently, the distinction cannot be made.
To decide for patients who might benefit from both medical and surgical therapy, evidence is required regarding three major factors: the long-term efficacy, the long-term QoL and the over- all costs. Finally, the patients’ preference should be taken into account, and to a lesser extent perhaps the doctor’s preference. However, the decisive factor should be evidence instead of pref- erence. Therefore, trials are needed to determine the mutual relations of therapies.
The optimal strategy for steroid-refractory ileocecal CD is currently under investigation in The Netherlands in the Laparoscopic Ileocolic Resection Versus Infliximab Treatment of Distal Ileitis in Crohn’s Disease (LIR!C) trial [62]. In this trial, a laparoscopic ileocolic resection is being compared with treatment with IFX for recurrent CD in the terminal ileum. Primary end points in this study are the costs and QoL. Patients are followed-up for 1 year after the start of treatment. The results of this trial can be expected in 2012 or 2013.
Five-year view
Thanks to the developments in basic research, a shift in the treatment paradigm might be expected in the long term. There is increasing evidence that CD is not one disease entity but that it is rather a group of diseases, all requiring different treatment. Genetic research has revealed various variants in genes, such as NOD2, that are associated with CD. Possibly, by mapping the genome of a CD patient, the future phenotype of the disease can be predicted to adjust the treatment to this prediction [63].

However, the solution and implementation of the genomic research path will probably remain future prospects over the next 5 years. In the meantime, clinical trials investigating the best treatment options for CD patients are critically important. At the same time, the developments of new antibodies against TNF or other cytokines may reveal interesting treatment targets. A good review of all the biologic therapies currently under investigation in different phases is presented in the article of Rutgeerts et al. [64]. All ‘-abs’ with their targets are described and an overview is given of which phase of research each of the products is.
In conclusion, no evidence is available pointing to a specific strategy, although more long-term evidence is available on surgical treatment. At present, all benefits and risks must be weighed carefully and discussed with the patient to decide what therapy path must be chosen. Trials are needed to be able to definitely answer the question ‘medical or surgical treatment?’
Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.

Key issues
• Ileocecal Crohn’s disease (CD) can be treated both medically and surgically.
• Medical therapy of ileocolic CD exists of a step-up approach starting with the least potent agents that suffice to keep the disease in remission.
• Anti-TNF therapy is effective in fistulizing, steroid-dependent and steroid and thiopurine-refractory CD; however, long-term efficacy in terms of cost effectiveness needs to be determined.
• A laparoscopic ileocolic resection leads to a quick restoration of quality of life and a low long-term re-resection rate.
• Patients who have disease activity in other regions than only at L1, or who have active perianal disease, severe extraintestinal manifestations or autoimmune comorbidity, should receive medical therapy.
• Patients with obstructive symptoms due to a fibrotic terminal ileum are best treated surgically.
• No evidence exists as to whether patients with steroid-dependant or refractory ileocecal CD, who do not meet the criteria detailed previously, should be treated medically or surgically.
• In the comparison of ileocolic resection versus medical therapy, evidence is needed on costs, safety and long-term efficacy.

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44 Bernklev T, Jahnsen J, Schulz T et al. Course of disease, drug treatment and health-related quality of life in patients with inflammatory bowel disease 5 years after initial diagnosis. Eur. J. Gastroenterol. Hepatol. 17, 1037–1045 (2005).
45 Feagan BG, Yan S, Bala M, Bao W, Lichtenstein GR. The effects of infliximab maintenance therapy on health-related quality of life. Am. J. Gastroenterol. 98, 2232–2238 (2003).
46 Loftus EV, Feagan BG, Colombel JF et al. Effects of adalimumab maintenance therapy on health-related quality of life of patients with Crohn’s disease: patient- reported outcomes of the CHARM trial. Am. J. Gastroenterol. 103, 3132–3141 (2008).
47 Casellas F, Rodrigo L, Nino P, Pantiga C, Riestra S, Malagelada JR. Sustained improvement of health-related quality of life in Crohn’s disease patients treated with infliximab and azathioprine for 4 years. Inflamm. Bowel. Dis. 13, 1395–1400 (2007).
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http://gidiv.ucsf.edu/course/things/Eshuis.pdf
Decision-making in ileocecal Crohn’s disease management: surgery versus
pharmacotherapy
Expert Rev. Gastroenterol. Hepatol. 4(2), 181–189 (2010)
Emma J Eshuis,
Pieter CF Stokkers and
Willem A Bemelman†
†Author for correspondence Department of Surgery, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands Tel.: +31 205 669 111
Fax: +31 205 669 285 [email protected]
Ileocecal Crohn’s disease (CD) can be treated medically as well as surgically. Both treatment modalities have been improved markedly in the last two decades, making CD more manageable. However, multidisciplinary research, addressing issues such as timing of surgery or medical treatment versus surgery, is scarce. Particularly in limited ileocecal CD, ileocolic resection might be a good alternative to long-term medical therapy. This review discusses the evidence on medical and surgical treatment options for ileocecal CD. It provides an aid in decision-making by discussing a treatment algorithm that can be used until further evidence on treatment is available.

Crohn’s disease (CD) is a chronic inflammatory bowel disorder that can affect the entire GI tract. In 25–30% of cases, disease activity is confined to the terminal ileum with or without cecal involvement [1]. Until 10–15 years ago, options in treating ileocecal CD were limited. Treatment focussed on symptom control rather than achieving long-term remission [2]. The medical treatment options consisted of 5-aminosalycitates (5-ASA), antibiotics and steroids. At that time, immune suppressors, such as meth- otrexate (MTX) or azathioprine (AZA), were already available. However, efficacy was not yet established and these therapies were rarely applied because of concerns of side effects [3]. In general, treatment consisted of a course of steroids for remission induction and 5-ASA compounds as maintenance therapy. Once refractory to steroids, patients were referred to the surgeon for ileocolic resection. Recurrent disease could lead to multiple resections with the inherent risk of complications requiring a deviating stoma and development of a short bowel syndrome. As a consequence, gastroenterologists were reluctant to send their patients to the surgeon and patients were chronically or repetitively treated with steroids. Surgery was considered to be the last option offered to patients with steroid-refractory disease.
In the last two decades treatment algorithms have changed. Evidence on the efficacy of immune suppressors has accumulated, proving to be efficient in maintaining remission in the majority of patients. Trials on 5-ASA showed that 5-ASA effectiveness is limited [4]. However, the most important development has been the discovery of biological anti-TNF therapy. Uncovering the important role of the proinflammatory cytokine TNF-a in the immune response has led to the development of monoclonal antibodies targeting this cytokine. These compounds appeared to be highly efficacious in the treatment of CD. Infliximab (IFX; 1998) and adalimumab (ADA; 2007) are registered treatments for moderate-to-severe CD and, in the USA, certolizumab pegol (2008) was added to the list [5,6].
During this time the surgical management of CD was also improving. Minimal invasive surgery, bowel sparing techniques and enhanced recovery programs after surgery have greatly improved the quality of surgery and the peri- operative management resulting in earlier recovery, less morbidity and superior long-term results. Particularly in limited localized ileocecal disease activity, surgery is an effective treatment strategy with a quick restoration of quality of life (QoL).

In tertiary referral centers for inflammatory bowel disease (IBD) patients are often seen in joint clinics and decision-making is often performed in multidisciplinary teams. However, little research has been undertaken on issues concerning the surgical and medical treatment in terms of efficacy, costs and QoL. The available literature consists of a few opinion papers concerning timing of surgery in the era of biological therapies [7–9] and guidelines [10–12] lacking definitive answers.
The aim of this review is to discuss the medical and surgical treatment options for ileocecal CD and to provide an aid in decision making by discussing a treatment algorithm that can be used until further evidence on the treatment is available.
Ileocecal CD
When Burril Crohn first reported the disease that we now know as CD, he described a regional ileitis [13]. In 25–30% of CD patients, the ileocecal junction is the only region where the disease is active [14].
Typical complaints of patients with active CD in the ileocecal region are abdominal pain in the lower right quadrant, persistent diarrhea, fever with or without anorexia, nausea and vomiting as signs of obstruction [15]. The stenosis is caused by a combination of irreversible fibrosis due to repetitive relapses and/or edema caused by inflammation.
Medical options
The most commonly applied treatment algorithm in the medi- cal management of CD is a step-up approach. In this approach, therapy is started with the least toxic agents first. If not sufficiently effective, more potent drugs will be added or started instead. Some gastroenterologists propose a more aggressive approach, arguing that with the step-up approach, agents with low efficacy are used for prolonged periods of time, while uncontrolled inflammation continues, resulting in tissue damage. The newly advocated approach is a top-down strategy with initially aggressive treatment with biologic therapy and early immune suppression [16]. Decision-making in top-down versus step-up strategies was recently addressed in a previous issue of this journal and is beyond the scope of this review [17,18].
The American and European guidelines agree that for drug induced remission, patients with mild ileal CD are best treated with budesonide [10–12]. Budesonide is an ethylcellulose-coated steroid that is released in the ileum. Owing to the low systematic bioavailability as a result of the high first pass metabolism (90%), budesonide optimizes the advantages of steroid therapy and at the same time minimizes the risk of systemic side effects [19]. In the Cochrane review by Seow et al. budesonide proved to be more effective than placebo or mesalamine for induction of remission in CD [20]. Although less effective when compared with conventional steroids, budesonide was associated with a lower rate of adverse events.
For patients with a moderate-to-severe flare of disease, oral steroids (prednisone) are indicated [10–12]. In patients who require steroids to induce remission, concomitant maintenance therapy consisting of AZA or 6-mercaptopurine (6MP) must be considered, or MTX in the case of intolerance to thiopurines [10–12]. 6MP and its prodrug AZA are efficient for induction of remission, but have a delayed onset of action. However, when started together with a steroid remission induction course, AZA has been shown to be effective as maintenance therapy once the steroids were tapered [21,22]. MTX was shown to be significantly more effective compared with placebo in inducing and maintaining remission (remission induction: MTX 39% vs placebo 19% [p = 0.025]; maintenance of remission: MTX 65% vs placebo 14% [p = 0.04]) [23,24]. In current treatment strategies it is mainly applied as maintenance therapy.
Patients having recurrent flares despite immunomodulating maintenance therapy or showing intolerance necessitating repetitive steroid courses, require an anti-TNF agent as the next step in the medical treatment algorithm [10–12]. The first biological anti-TNF agent registered for the treatment of CD was IFX. In the USA it was approved by the US FDA in 1998, followed by approval in Europe in 1999. IFX is a chimeric human–murine antibody binding membrane bound as well as free soluble TNF, thereby neutralizing proinflammatory and regulatory actions of TNF. Multiple trials have established IFX for remission induction and maintenance therapy [25–27]. In 2007, the fully human anti-TNF agent ADA was added to the biological drug armamentarium, showing similar results in inducing and maintaining remission in ileocolonic CD [28–30].
Both IFX and ADA have shown clear efficacy in inducing remission (responses 65 and 58% in the large IFX trials [25,27]; 59% response at week 4 of the large ADA trial [28]). However, after 1 year only 40–50% of responding patients still experience benefits from these agents, as a large proportion of patients will lose response to these drugs [31,32]. In patients who became intolerant to IFX or who lost response, the Gauging Adalimumab Efficacy in Infliximab Nonresponders (GAIN) trial, a double-blind randomized trial, showed that ADA was significantly more efficient compared with placebo in restornig remission [33]. However, the gain was limited: after 4 weeks, remission was achieved in only 21% of patients (34 out of 159) in the ADA group versus 7% in the placebo group.
Safety of medical therapy
The long-term safety of medical therapy for CD remains to be determined. Since most medical therapies in CD are immune-suppressive there is a risk of developing opportunistic infections. In a large case control study, the use of corticosteroids, AZA/6MP and IFX was shown to be associated significantly with the development of opportunistic infections in IBD patients, especially when the compounds are used in combination [34]. A large cohort study recently showed that thiopurine use (AZA or 6MP) for IBD was associated with an increased risk of developing lymphoproliferative disorders (multivariate adjusted HR between patients receiving thiopurines and those who never received thiopurines: 5.28 [95% CI: 2.01–13.9]) [35]. A debate on the combined therapy of immuno- modulating agents, such as AZA or 6MP, and anti-TNF therapy is ongoing [36–38]. On one hand, concomitant immunomodulating therapy was shown to suppress the chance of developing antibodies against IFX, thereby preserving efficacy of IFX [39] and resulting in higher response rates [40]. On the other hand, emerging reports on hepatocellular T-cell lymphoma in young CD patients on anti-TNF in combination with thiopurines have made gastroenterologists reluctant to combine immune suppression for longer periods [41]. A study claiming equivalent efficacy of maintenance for IFX mono therapy and combined immune suppression is flawed by lack of power [42]. Other studies addressing the issue of tapering combined immune suppression are currently being undertaken [43,101].
QoL in medical treatment
Bernklev et al. found in a large cohort study that patients with CD have a significantly reduced QoL owing to frequent relapses, repetitive steroid courses, side effects of immunomodulating therapy or extra intestinal manifestations [44]. Feagan et al. investigated the QoL of patients receiving IFX remission induction and maintenance therapy for up to 1 year in the patients participating in A Crohn’s Disease Clinical Trial Evaluating Infliximab in a New Long-
Term Treatment Regimen (ACCENT) I Trial [45]. In this double-blind randomised trial, patients received IFX remission induction and maintenance therapy. The authors concluded that IFX therapy significantly improved QoL compared with the QoL in responders before therapy. This QoL remained statistically improved in those patients receiving IFX maintenance therapy compared with placebo receivers. A similar study has been performed for ADA (Crohn’s Trial of the Fully Human Antibody Adalimumab for Remission Maintenance [CHARM] trial), with similar conclusions [46]. However, no QoL data exist for patients on maintenance therapy with IFX or ADA compared with healthy controls. It might be hypothesized that the impaired QoL in patients with long-lasting immunomodulating therapy also applies for patients on long-term biological therapy. Moreover, data on QoL in patients on anti-TNF therapy for more than 1 year are scarce. Casellas et al. measured QoL in CD patients for up to 4 years after the start of IFX maintenance therapy [47]. However, QoL was only measured in those patients who remained in remission. The majority of patients relapsed and had a decline in quality of life but were excluded from the study, leaving the data unsuitable for interpretation.
Costs
Up to the point that biologicals are prescribed, costs for maintenance therapy remain low. However, a significant number of patients will require further treatment after failed steroid and immunomodulating therapy. Currently, gastroenterologists generally prescribe biological therapy.
In The Netherlands biological therapy is expensive; 100 mg of IFX costs €570. This implies that costs for a patient with a weight of 75 kg who starts IFX remission induction and maintenance therapy will accumulate to a total sum of €17,000 in 1 year, apart from costs for daycare at the hospital, estimated at €500 per infusion. Likewise, 40 mg of ADA costs €1065 in The Netherlands; 1 year of therapy (one injection of 80 mg followed by 40 mg every 2 weeks) totals €28751.49 (Figure 1).
Bodger et al. performed a Markov analysis to assess the cost–effectiveness of biological therapy. They concluded that in responders, compared with standard therapy, both IFX and ADA may represent a cost effective use of healthcare resources for up to 4 years, since costs fell below the £30,000 per quality- adjusted life years threshold for cost–effectiveness in the UK [48]. The Canadian Agency for Drugs and Technologies in Health, however, has published a cost effectiveness analysis regarding anti-TNF drugs for the treatment of refractory IBD, comparing them with surgery and with conventional treatments [102]. The conclusion was that costs associated with anti-TNF treatments are high and that anti-TNF treatment might not be cost effective. Since anti-TNF treatment might not be cost effective, it must be used selectively. Other alternatives, such as surgery become more important. A real-life comparison of anti-TNF and surgery for ileocecal CD disease in terms of costs and quality-adjusted life years is needed.
Surgical options
The surgical treatment of ileocecal CD consists of an ileocolic resection. During the past few decades, surgical research has been focussing on the comparison of laparoscopic and open surgery. These studies provided evidence on short and long-term results of both approaches. Short-term studies showed that QoL is quickly restored after the ileocolic resection. Long-term studies revealed a low recurrence rate, indicating that ileocolic resection is a very effective treatment for localized ileocecal CD.
Short-term outcomes after ileocolic resection
Four systematic reviews describing the short-term results after a laparoscopic versus open ileocolic resection have been published. These reviews were based on 12–16 studies including two randomized trials [49,50]. Polle et al. reported a postoperative surgical reintervention rate of 0–8.3% in the different studies analyzed in their review (Table 1) [51]. Overall morbidity was 15.3% (Table 2). One might hypothesize that these results were achieved in specialized institutions, thereby not reflecting daily practice. A nationwide analysis of all ileocolic resections performed in France in the period 2000–2004 showed a similar overall morbidity rate of 15% in 49,609 procedures [52]. In-hospital mortality in this cohort was 0.9% and was significantly higher after an open approach (0.9% in open operated patients compared with 0.2% after laparoscopic resection; p ≤ 0.01).
Several studies have investigated the risk of postoperative complications in the setting of prior anti-TNF therapy. A systematic review published in 2006 concluded that there was no increased rate of postoperative complications associated with immuno-modulator use [53]. More publications have appeared since then, but these studies have shown conflicting results [54,55]. It is, there- fore, as yet unknown whether anti-TNF or immunomodulator therapy should be avoided in the preoperative setting. Maartense et al. measured QoL before and during the 3 months after the initial resection [49]. Patients had a quick restoration of QoL after surgery: a short deterioration was resolved after 2 weeks, and after 3 months QoL had increased significantly (p < 0.0001 compared with the baseline measurement). With regard to the comparison of laparoscopy and open surgery, all reviewers concluded that laparoscopy had short-term benefits over open surgery.
Long-term results
Long-term follow-up data of ileocolic resection also originate from trials that compared the laparoscopic and open techniques. The two most recent long-term studies are follow-up studies from two randomized trials [56,57]. In a cohort of 56 patients with a median follow-up of 10.5 years, Stocchi et al. found an overall recurrence rate of 52% [56]. However, the recurrence rate requiring re-resection was 28.5%, and only an additional 9% of patients required a readmission to treat the disease medically. This means that half of patients remained disease free until 10 years after the resection. Of the other half of patients, one third of patients could be managed in an out-patient setting.
Our own data showed an overall clinical recurrence rate of 38% with only five out of 55 patients (9%) requiring re-resection [57]. Median follow-up in this study was 6.8 years. Long-term QoL in this study was comparable to the QoL of healthy controls on most subscales subscribing the efficacy of laparoscopic ileocolic resection. Important features of laparoscopic surgery were a superior cosmesis and fewer incisional hernias.
Costs
In the study of Maartense et al., median overall costs were significantly lower after a laparoscopic approach compared with the open technique (Figure 1) [49]. The median costs, including relaparotomies, hospital stay and readmission costs, were €6.412 for the laparoscopic procedure and €8.196 for the open approach. Young-Fadok et al. calculated similar costs [58]. After a follow-up of 6.8–10.5 years, no additional costs were made apart from the periodical out-patient visits in 50–60% of patients. The remaining patients had extra costs as result of a relapse requiring medical or surgical treatment.
Early versus late surgery
Aratari et al. retrospectively compared outcomes of patients who underwent surgery at time of diagnosis with those of patients who had surgery during the course of the disease [59]. They concluded that the incidence of clinical recurrence requiring immuno-suppressive therapy was significantly lower in the early-surgery group, indicating that early surgery might lead to a prolonged clinical remission. Owing to the retrospective, nonrandomized design of the trial, the comment on this study is that the two groups were not comparable: in the early-surgery group, the surgery was often performed because of clinical need, and not to investigate a top-down approach, while the late surgery patients had more severe disease activity associated with a shorter disease-free survival [60].
From a patient perspective, an older but interesting study is that of Scott and Hughes from 1994 [61]. A total of 80 patients who underwent an ileocolic resection were questioned if they would - in retrospect - have preferred an earlier or later resection, or at the same time as it was done. Of the 70 recipients, 74% answered that they would have wanted an earlier resection, and not one patient would have preferred their operation to have been later.
Since this study lacks a control group it is a biased study. It is, however, the only evidence available about the patients’ opinion on timing of surgery and, therefore, worth mentioning.
In summary, the major short-term benefit of an ileocolic resection is the quick restoration in QoL due to the removal of the diseased bowel segment at the expense of a (small) risk of severe complications. When looking at the long-term follow-up a low recurrence rate requiring re-resection was found, but the overall relapse rate was also relatively low.
Expert commentary: medication or surgery?
The treatment success of IFX in therapy-resistant CD is evident and surgical resection is commonly appreciated as a negative outcome in the treatment of CD. As a consequence, surgical resection as a treatment option is often overlooked and patients are frequently unnecessarily treated with consecutive courses of immunosuppressant with a significant burden on the QoL. Isolated ileocecal CD in particular offers the alternative of surgical resection and may have gains in cost–effectiveness and QoL that extend far beyond the benefits of medical therapy.
Both the medical and surgical strategy can be advocated on clinical arguments. On one hand, medical treatment can prolong resection-free survival, thereby preventing the risks of surgery; on the other hand, studies have shown that resection often leads to a quick restoration of QoL with a low long-term recurrence rate. Moreover, long-term results of laparoscopic ileocolic resection are well established now, while, by contrast, little is known about the efficacy and QoL of long-term immunomodulating therapy and treatment with biologicals.
Guidelines differ in their recommendations. The European guidelines state that for severely active localized ileocecal disease not responding to conventional therapy, “infliximab should be considered ... although surgical options should also be considered and discussed” [10]. The American College of Gastroenterology practice guideline states that surgery is advocated for “neoplastic/preneoplastic lesions, obstructing stenoses, suppurative complications, or medically intractable disease”, suggesting that all medical options should have been tried before turning to surgery [11]. It is, however, noted that with the better postoperative maintenance schemes and appropriate surgery, the prolongation of ineffective medical management is no longer justified to ‘avoid’ surgery.
In the decision of whether to treat surgically or medically, it is important to take several factors into consideration that preclude one of the treatment options beforehand (see algorithm, Figure 2). First, it is important to rule out disease activity elsewhere, because in these cases, an ileocolic resection will not suffice. In case of severe extraintestinal manifestations or autoimmune comorbidity, medical therapy is indicated to treat both disease entities. Patients with active perianal fistulas concomitant with ileocecal CD are best treated with anti-TNF. On the contrary, however, patients with obstructive symptoms due to a fibrotic terminal ileum are best treated surgically, since medication will have no effect. In clinical practice the distinction between a fibrotic stricture and inflammatory stenosis may be difficult. Prestenotic dilatation and absence of wall thickening and an inflammatory infiltrate on MRI indicate a predominant fibrotic component, whereas ulceration and edema of the mucosa and the bowel wall point towards an inflammatory stenosis. Frequently, the distinction cannot be made.
To decide for patients who might benefit from both medical and surgical therapy, evidence is required regarding three major factors: the long-term efficacy, the long-term QoL and the over- all costs. Finally, the patients’ preference should be taken into account, and to a lesser extent perhaps the doctor’s preference. However, the decisive factor should be evidence instead of pref- erence. Therefore, trials are needed to determine the mutual relations of therapies.
The optimal strategy for steroid-refractory ileocecal CD is currently under investigation in The Netherlands in the Laparoscopic Ileocolic Resection Versus Infliximab Treatment of Distal Ileitis in Crohn’s Disease (LIR!C) trial [62]. In this trial, a laparoscopic ileocolic resection is being compared with treatment with IFX for recurrent CD in the terminal ileum. Primary end points in this study are the costs and QoL. Patients are followed-up for 1 year after the start of treatment. The results of this trial can be expected in 2012 or 2013.
Five-year view
Thanks to the developments in basic research, a shift in the treatment paradigm might be expected in the long term. There is increasing evidence that CD is not one disease entity but that it is rather a group of diseases, all requiring different treatment. Genetic research has revealed various variants in genes, such as NOD2, that are associated with CD. Possibly, by mapping the genome of a CD patient, the future phenotype of the disease can be predicted to adjust the treatment to this prediction [63].

However, the solution and implementation of the genomic research path will probably remain future prospects over the next 5 years. In the meantime, clinical trials investigating the best treatment options for CD patients are critically important. At the same time, the developments of new antibodies against TNF or other cytokines may reveal interesting treatment targets. A good review of all the biologic therapies currently under investigation in different phases is presented in the article of Rutgeerts et al. [64]. All ‘-abs’ with their targets are described and an overview is given of which phase of research each of the products is.
In conclusion, no evidence is available pointing to a specific strategy, although more long-term evidence is available on surgical treatment. At present, all benefits and risks must be weighed carefully and discussed with the patient to decide what therapy path must be chosen. Trials are needed to be able to definitely answer the question ‘medical or surgical treatment?’
Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.

Key issues
• Ileocecal Crohn’s disease (CD) can be treated both medically and surgically.
• Medical therapy of ileocolic CD exists of a step-up approach starting with the least potent agents that suffice to keep the disease in remission.
• Anti-TNF therapy is effective in fistulizing, steroid-dependent and steroid and thiopurine-refractory CD; however, long-term efficacy in terms of cost effectiveness needs to be determined.
• A laparoscopic ileocolic resection leads to a quick restoration of quality of life and a low long-term re-resection rate.
• Patients who have disease activity in other regions than only at L1, or who have active perianal disease, severe extraintestinal manifestations or autoimmune comorbidity, should receive medical therapy.
• Patients with obstructive symptoms due to a fibrotic terminal ileum are best treated surgically.
• No evidence exists as to whether patients with steroid-dependant or refractory ileocecal CD, who do not meet the criteria detailed previously, should be treated medically or surgically.
• In the comparison of ileocolic resection versus medical therapy, evidence is needed on costs, safety and long-term efficacy.

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