© Kapil Sahnan
Laparoscopic ileocaecal resection versus infliximab for terminal ileitis in Crohn’s disease: A randomised controlled, open-label, multicentre trial
Ponsioen CY, de Groof EJ, Eshuis EJ, Gardenbroek TJ, Bossuyt PMM, Hart A, et al.
Lancet Gastroenterol Hepatol. 2017;2:785–92.
The LIR!C group recently published a multicentre, randomised controlled trial (RCT) comparing infliximab (IFX) with ileocaecal resection for patients with non-stricturing terminal ileitis. The study demonstrates real-world evidence that surgery is a good option in terminal ileal Crohn’s Disease (CD). Patients with limited non-stricturing (<40 cm) terminal ileal disease who have failed conventional medical therapy benefit equally, in terms of a comparable health-related quality of life (QoL), from either escalation to IFX or resection. Prior to this study, resection for non-stricturing disease has been reserved for non-responders to biologics.
This open label RCT was conducted in 29 centres across the Netherlands and the United Kingdom over 7.5 years in accordance with the 2016 ECCO Guidelines [1,2]. Patients aged 18–80 years, in whom conventional therapy had failed (failure to respond to ≤3 months of glucocorticosteroids, thiopurines or methotrexate), and who did not have stricturing disease (pre-stenotic dilation or absence of inflammation on the screening MR enterography), were randomised to receive laparoscopic ileocaecal resection or IFX. Patients with prior ileocaecal resection, disease length >40 cm, abdominal abscesses or ASA scores ≥III were excluded.
Adaptive randomisation resulted in equally weighted arms. Between May 2008 and October 2015, 143 patients were included (33% male) with a median age of 27 years (IQR 22–40). Eventually, 65/70 patients who were randomised started IFX and 70/73 had surgery. Resections were performed laparoscopically (single or multiple port) with pre-/postoperative immunosuppression at the discretion of the treating physician. Baseline characteristics for both groups were similar, except for smoking status, which was higher in the IFX arm (45%) than in the surgical arm (31%). The median follow-up was 4.0 years, with long-term follow data available for 139/143 patients.
The primary outcome measure was QoL on the Inflammatory Bowel Disease Questionnaire (IBDQ) at one year. The trial was not designed to detect non-inferiority, but the estimated mean difference and the corresponding 95% CI (6.1 points, -4.2 to 16.4, p=0.25), suggested that QoL after ileocaecal resection is similar to that with IFX. Patients’ perception of body image pre/post surgery, the days patients were unable to participate in social life in terms of days of sick leave and morbidity (additional procedures and hospital admissions) were comparable. The rate of endoscopic recurrence at one year, evaluated by a single reader, was 16% for the IFX group and 21% for the resection group.
As expected, generic QoL (SF-36) initially decreased in the resection group. This improved and the scores at 6, 9 and 12 months were significantly higher in the resection group. The estimated mean difference was 5.6 points (95% CI –0.4 to 11.6). This difference was most marked in the physical component of the SF-36 score; the authors hypothesise that this may have been due to the use of a generic QoL score and the difference between a single episode intervention (surgery) versus a multiple episode intervention (repeat IFX infusions). Alternatively, some patients on IFX may have a “grumbling” non-functioning segment of bowel, perhaps supported by the progression to resection within 1.5 years in over a third of patients.
In the IFX group, 3% of patients had treatment-related serious adverse events (pneumonia and perianal abscess). In the resection group, 11% of patients had complications; of these, three had an ileus, three had an anastomotic leak and two had intra-abdominal abscesses/haematomas. The resections were performed in tertiary and teaching hospitals and these results may not reflect the circumstances and outcomes in non-specialist hospitals, where open surgery may be more likely.
Approximately two-thirds (44/70; 63%) of patients in the IFX arm and the majority (67/73, 92%) in the surgical arm completed their treatment. Of note, 26/70 (37%) of the patients assigned to IFX had resection [median 70 weeks (IQR 27–172)] and 19/73 (26%) assigned to surgery received IFX [median 112 weeks (56–177)]. The authors acknowledge that during the study period there was an increase in drug level monitoring, and also combination therapy of IFX with azathioprine has been demonstrated to be superior , which may explain why the crossover was most marked in the IFX arm. However, the proportion of patients on concomitant immunomodulatory therapy was higher in the IFX group than in the resection group and these decisions were left to the physician’s discretion.
One limitation of the study was its duration, which was likely due to the recruitment process as well as the relatively long-term follow-up. The authors acknowledge that many patients were unwilling to be randomised, an aspect which is probably under-reported. This raises interesting questions about how to randomise patients in future trials evaluating medical and surgical treatment. IBD patients are often young, computer literate and well versed in their condition. Minimising dropout through appropriate counselling and study designs, such as the use of a patient preference model, is crucial. The evidence basis which LIR!C has provided will no doubt make recruitment in future research easier.
LIR!C has undoubtedly informed future research directions and new trials should look to explore the role of optimised medical treatment regimes, new biologics and comparison between ‘step-up’ versus ‘top-down’ approaches. Having identified a role for surgery in these patients, the surgical intervention could be evaluated further with respect to timing (i.e. in an immunosuppressant-naïve group) and open/laparoscopic approaches. In addition, other outcomes such as cost-benefit analysis and QoL trade-off need evaluation.
Surgery can be offered as a valid alternative, earlier in the treatment pathway, for patients with limited ileocaecal disease and not just for those who have stricturing disease or have failed biologics. QoL scores for patients who underwent laparoscopic ileocaecal resection and patients who received IFX were similar at one year in all domains, including physical and mental components, and surgery can be considered an acceptable alternative to IFX.
Major complications in the resection arm were demonstrated in one in 20 patients and over a quarter needed IFX within the 4-year follow-up period. The patients who had surgery were not significantly adversely affected with respect to their body image or cosmesis. Over a third of the patients who received IFX needed surgery within the follow-up period.
The optimal therapeutic approach to ileocaecal CD remains unclear but this study has expanded on the options available to both patients and clinicians. The results of this trial arm clinicians with equipoise for medical and surgical treatment strategies for terminal ileitis. To some patients, surgery may be a welcome option that offers freedom from repeated infusions, comparable (un)scheduled admissions and avoidance of biologics when planning a family. A tailored approach incorporating patient preference is mandated to facilitate shared decision-making and an informed consent process.
1. Gomollón F, Dignass A, Annese V, et al. 3rd European Evidence-based Consensus on the Diagnosis and Management of Crohn’s Disease 2016: Part 1: Diagnosis and medical management. J Crohn’s Colitis. 2017;11:3–25.
2. Gionchetti P, Dignass A, Danese S, et al. 3rd European Evidence-based Consensus on the Diagnosis and Management of Crohn’s Disease 2016: Part 2: Surgical management and special situations on behalf of ECCO. J Crohn’s Colitis. 2017;135–49.
3. Colombel JF, Sandborn WJ, Reinisch W, et al. Infliximab, azathioprine, or combination therapy for Crohn’s disease. N Engl J Med. 2010;362:1383–95.
|Kapil Sahnan is a surgical trainee in the United Kingdom. He is currently undertaking his PhD at the Fistula Research Unit, St Mark’s Hospital with Robin Phillips and Ailsa Hart. The focus of his research is perianal Crohn’s Disease and advanced proctology.||
Kapil Sahnan © Kapil Sahnan