Abbreviations:
BE (Barrett's esophagus), BTX-A (botulinum toxin type A), ESD (endoscopic submucosal dissection), RFA (radiofrequency ablation), SCC (squamous cell cancer)Endoscopic resection is widely accepted as a curative treatment of early esophageal neoplasia. Histologic assessment of resected specimens provides accurate local tumor staging and grading. A variety of criteria allow identifying patients with a very low risk of lymph node metastases so that additional treatment, such as surgery or radiochemotherapy, can be avoided. En bloc resection is recommended for superficial squamous cell cancer (SCC) to facilitate complete histologic evaluation and to avoid missing even small areas with advanced features, such as invasion of lymphatic vessels or cancerous involvement of the muscularis mucosae (m3) and even deeper layers. For this purpose, endoscopic submucosal dissection (ESD) should be the preferred method for resection of early SCC. It is superior to EMR in terms of histologically complete resection (R0) and local tumor recurrence even in cases of small lesions.
1
, 2
, 3
By contrast, ESD has not shown any advantages over EMR for resection of early Barrett’s neoplasia.1
, 4
Indeed, it more frequently achieves R0 resection, but the risk of missing minor histologic features in Barrett’s esophagus (BE) neoplasia may be clinically less relevant than with SCC. In particular, cancerous invasion of m3 is associated with a very low risk of lymph node metastases in BE, in contrast to an incidence of 8% to 18% in SCC.5
Recurrences or metachronous neoplasia occur in as many as one third of patients after EMR of early BE neoplasia. However, the combination of EMR of neoplasia and radiofrequency ablation of the remaining intestinal metaplasia reduced the recurrence rate to 4% after a median follow-up period of 27 months in a prospective multicenter trial.6
It seems very unlikely that ESD can improve these excellent results even further. However, it may be considered in selected cases of more advanced BE neoplasias.1
, 4
Esophageal ESD and EMR have become safe procedures with a low rate of short-term adverse events as a result of technical improvements and various endoscopic options to manage intraoperative events like bleeding or perforation. In contrast to the short-term safety of ESD and EMR, the formation of an esophageal stricture is a common, and severe, delayed adverse event after a widely extended resection. The frequency of strictures after ESD of esophageal SCC mainly depends on the circumferential extent of dissection. A mucosal defect of more than three quarters causes stricture rates of 70% to 90%; these rates approach 100% after complete resection of the circumference.
7
, 8
, 9
The incidence seems to be similar after extended resection of early BE neoplasia, particularly when the aim is complete eradication of BE. A recent retrospective trial reported on strictures in 60% of 75 patients after ESD of BE neoplasia with large safety margins.10
The risk seems to be comparable with widespread piecemeal EMR, indicating that risk is associated with the extent of resection and is not related to the technique.11
A recent multicenter randomized trial showed a stricture rate of 88% after stepwise radical EMR of BE neoplasia, which was significantly higher (P < .001) than a rate of 14% after a combination of EMR of neoplasia followed by radiofrequency ablation of remaining intestinal metaplasia.12
Even complete EMR for short-segment BE with early neoplasia caused strictures requiring repeated endoscopic dilation in approximately one third of patients.13
Wide resection of the circumference is considered to be the most important risk factor for the development of strictures. Longitudinal extent of resection and depth of neoplastic invasion have been determined to be additional predictive factors.
8
, 14
Stricture formation after endoscopic resection substantially decreases a patient’s quality of life, and repeated endoscopic dilation sessions are frequently needed. A median number of 4 sessions and as many as 19 procedures were required for the management of strictures after stepwise radical EMR of BE neoplasia.
12
These interventions are inconvenient for the patients and cause perforation in approximately 1% of cases.15
Therefore, there is a strong demand for stricture prevention, particularly in high-risk candidates with extended resection of early esophageal neoplasia.Prophylactic considerations should include the pathophysiology of postprocedural stricture formation. The process seems to be mainly correlated with delayed mucosal healing, severe inflammation causing deeper ulceration, fibrosis, and atrophy of the muscularis propria. Specimens surgically obtained from patients with post-ESD strictures show rich collagen fibers with inflammatory cells in the submucosa and atrophic changes of the muscle layer. Postprocedural esophageal dysmotility may also cause dysphagia after resection.
15
, 16
A large variety of interventions for stricture prevention, based on the pathophysiology of formation and risk factors, was investigated. Nearly all of the clinical trials were performed in Asian patients with early esophageal SCC. Studies of preventive endoscopic dilation showed disappointing results in terms of the large number of required procedures, worsening quality of life for patients, and a risk of dilation-associated adverse events.
17
A small randomized trial in patients with extended ESD of early esophageal SCC indicated that the implantation of a fully covered esophageal stent significantly reduced the risk of stricture formation in comparison with a control group.18
However, a recent uncontrolled series demonstrated that early metal stent implantation after widespread EMR of BE neoplasia was associated with symptomatic strictures in 57% of 14 patients. More than one third of these strictures were considered to be stent related.19
The aim of local or systemic administration of steroids is to reduce injury-induced inflammation and to decrease the formation of granulation tissue. Contined treatment with steroids may inhibit collagen synthesis and cross-linking.
20
A recent meta-analysis of steroid administration for the prevention of post-ESD esophageal strictures included 5 randomized controlled trials, 5 cohort studies, and 2 case-control studies with a total number of 513 patients.20
The results indicated that treatment with steroids reduced the risk of strictures on average by 60% and decreased the need for dilation. Local injection of steroids seems to have an effect similar to that of systemic administration in terms of structure development, and it is superior in terms of number of dilation sessions. A systematic review of methods for the prevention of esophageal stricture after ESD showed similar results.21
However, interpretation of these analyses should consider the major design limitations of most of the trials, particularly in view of small case volumes and the large variation of methods, doses of steroid administration, and follow-up protocols. One of the comparative trials showed a stricture rate of only 10% after intralesional steroid injection.22
Interestingly, the same group recently reported on refractory strictures despite steroid injection in 19% of 127 cases.23
The variety of methods and results suggest that treatment with steroids is advantageous but has limited efficacy, and the level of evidence is low. In addition, it should be considered that local administration of steroids after wide endoscopic resection is not without risks. Delayed epithelialization could facilitate bacterial infection, causing extension of inflammation and delayed healing. In addition, inhibition of fibrosis and steroid-induced ulceration may weaken the esophageal wall and increase the risk of dilation procedures. Systemic administration of steroids can cause other adverse events resulting from immune suppression, or the development of psychiatric disturbances or diabetes.15
A promising approach is postprocedural oral treatment with viscous budesonide slurry twice daily for 6 weeks. It reduced the incidence of esophageal stricture formation after complete EMR of short-segment BE neoplasia from 37% to 14% (P = .03) without causing any side effects, according to a recent small randomized controlled trial.24
Other small studies indicate that local injection of mitomycin C or oral administration of N-acetylcysteine seems to reduce the risk of stricture formation after esophageal ESD, which could be due to the antiproliferative and antifibrotic effects of those substances.25
, 26
Recent advances in regenerative medicine offer additional new options for early repair and replacement of injured tissue after widespread endoscopic resection.27
Feasibility trials in humans suggest that tissue-engineered cell sheets and therapy with temporary scaffolds developed from biodegradable materials seem to promote the re-epithelization of the resection wounds with less scar and stricture formation.28
, 29
However, a variety of technical difficulties, such as the delivery of sheets to the esophageal wall, remain, and comparative trials are warranted.15
For the first time, Wen et al
30
have investigated the feasibility and efficacy of the endoscopic injection of botulinum toxin type A (BTX-A) for the prevention of strictures after ESD of early esophageal SCC in a randomized clinical trial. Previous studies had shown that BTX-A decreases the fibrosis of surgical wounds, prevents widening of scars, and could decrease collagen deposition during tissue repair.31
The authors’ study included 67 patients in whom ESD exceeded one half of the esophageal circumference. The patients were randomized into a control group and a group of patients in whom BTX-A was injected immediately after ESD. Follow-up endoscopy was performed 6 weeks after the procedure and on demand in patients with dysphagia. Strictures were repeatedly treated with bougienage until an endoscope could pass through the stenotic area. Dysphagia grading scores and quality-of-life questionnaire scores were recorded at 12 weeks. The results of this innovative trial indicate that local injection of BTX-A after extended ESD of esophageal SCC significantly reduced the rate of stricture formation as the primary endpoint (11.4% vs 37.8%, P < .05, on an intention-to-treat analysis) and the number of required dilation procedures compared with the control group. No serious adverse events were observed during or after BTX-A injection. The authors conclude that the treatment is effective and safe in preventing post-ESD strictures.30
They should be congratulated on their interesting approach and their evaluation in this prospective randomized trial. The results are very promising and are similar to the administration of steroids, with potentially fewer side effects. However, interpretation of this single-center study should consider some limitations. The sample size calculation was based on patients with mucosal defects more than two thirds of the circumferene, considering a stricture rate of 60% in a control group. Only 24 patients would have to be enrolled to demonstrate the expected efficacy of BTX-A injection. In contrast to this calculation, 3 times more patients were enrolled, and the inclusion criteria were extended to lesions that exceeded one half instead of two thirds of the circumference. This approach may have allowed the continuing enrollment of patients until more patients with extended lesions were included and a significant difference between both groups was reached. A subgroup analysis of the results indicated that patients with lesions smaller than two thirds of the circumference did not benefit from BTX-A injection. Unfortunately, the longitudinal extent of lesions and the size of resected specimens were not reported, although these factors are also predictive of stricture formation.8
, 14
Depth of invasion was the only reported histologic feature. Tumor grade, completeness of resection, and vascular involvement were not mentioned, so that the 2 groups cannot be compared in this respect. It is surprising that obviously no case of submucosal cancerous invasion or any other advanced histologic features was registered. No patient underwent additional therapy even though 13 patients had deep mucosal invasion (m3) and were at risk of lymph-node metastases.The authors clearly explain the beneficial effect of BTX-A on tissue regeneration. As in many other studies on ESD, the vertical level of dissection was not reported. It remains undetermined whether the submucosa was completely removed or dissected in, for example, the middle layer, which would be appropriate for evaluation of the resected specimen and may facilitate re-epithelization. Injections were placed deeply at the level of the muscularis propria with only 10 units of BTX-A each at 10 different sites. It is difficult to imagine that this approach has a substantial impact of the healing of large wounds. Nevertheless, it seemed to cause a lower stricture rate than in the control group. This primary endpoint was defined as a lumen with a diameter of less than 9.8 mm, which did not allow passage of a standard endoscope. This does not seem to be an objective factor because the success of negotiating a narrow lumen depends on the pushing force during advancement of the endoscope. To overcome a potential bias, the operator who determined stricture formation was blinded to randomization. Patients who received BTX-A injection also benefited in the dysphagia grading score. However, this score was determined 12 weeks after ESD, and it remains unclear how many patients had received bougienage at the 6-week follow-up or on demand before the evaluation.
How do the results of the study compare with other methods of stricture prevention after endoscopic widespread esophageal resection? BTX-A injection is promising because it is easy to apply and seems to be as effective as the administration of steroids, with the potential advantage of fewer adverse events. However, further evaluation in a large multicenter randomized trial is needed to enable comparison of this new approach with the injection of steroids and a control group. Oral administration of N-acetylcysteine or viscous budesonide slurry is another attractive approach because of the ease of use and safety. Further carefully designed multicenter trials should also consider combinations of different methods, including temporary stent placement, as was done in patients with complete circumferential resection in the study of Wen et al.
30
Regenerative medicine therapies promise better results, but a variety of technical difficulties have to be solved, and their cost effectiveness has to be evaluated.Despite progress in the prevention of stricture formation, the effect of various measurements is still limited. The incidence of strictures strongly correlates with the size of resection and substantially increases if it exceeds more than two thirds of the esophageal circumference. Careful delineation of the horizontal extent of neoplasia and precise cutting close to safety margins are needed to minimize the size of the defect. It has not been proved but might be of advantage to avoid complete resection of the submucosa and to leave its deeper layers. In contrast to SCC, wide resection of early BE neoplasia is less frequently needed and should be limited to selected patients with advanced lesions. The vast majority of cases of neoplastic BE can be well managed with EMR of focal lesions followed by radiofrequency ablation of the remaining intestinal metaplasia. Therefore, measurements for preventing strictures can mainly be limited to patients with extended superficial SCC, who are rarely seen in Western countries. Large clinical trials that are needed to compare different methods and their combinations probably only can be performed in Asian countries. However, a close international collaboration in basic research and medical engineering is required to develop new techniques and strategies to study and modify tissue healing after endoscopic resection at various sites of the GI tract.
Disclosure
The author disclosed no financial relationships relevant to this publication.
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- Prevention of esophageal strictures after endoscopic submucosal dissection with the injection of botulinum toxin type AGastrointestinal EndoscopyVol. 84Issue 4
- PreviewThe use of endoscopic submucosal dissection (ESD) for management of widespread superficial esophageal squamous carcinoma is closely associated with esophageal stenosis. We investigated the efficacy and feasibility of endoscopic injection of botulinum toxin type A (BTX-A) for preventing esophageal strictures after ESD for superficial esophageal squamous carcinoma.
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