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Oesophageal strictures following circumferential endoscopic submucosal dissection (cESD) for extended early oesophageal cancer remain an unresolved issue since they are often treatment-refractory. We present a strategy to use topical steroids for submucosal injection during ESD followed by two postprocedural injection sessions. Doses between 70 and 120 mg of triamcinolone (2 mg/mL) were used. During a follow-up of a mean of 6 months (range: 3–12 months), only 1/9 of patients developed a stricture which resolved after one dilatation session. No adverse events were noted. This concept should be tested further in larger prospective trials.
In more detail
Oesophageal stricture after cESD is emerging as a major concern given that it occurs at a high rate of 100% and leads to poor quality of life.1–5 Despite the proposal of several approaches to prevent post-cESD stricture, these strategies have not produced satisfactory outcomes or have specific limitations (online supplemental table S1). To address this issue, we have developed a novel and easy-to-perform method of administering steroids called the submucosal steroid pre-injection strategy (SSPS). This prospective, single-arm, multicentre study aimed to demonstrate the efficacy and safety of SSPS for preventing post-cESD stricture and report the results of our preliminary study.
Supplemental material
Patients with superficial oesophageal cancer expected to result in a post-ESD mucosal defect involving the entire oesophageal circumference were consecutively recruited at three hospitals. The oesophageal lesions are removed by cESD, and SSPS is used to prevent post-cESD stricture. The schematic diagram of the key SSPS steps and a real-life case (case 2) are illustrated in figures 1 and 2 and online supplemental video 1. The SSPS involves three sessions of triamcinolone acetonide (TA) injection. The first session is performed simultaneously with the start of cESD. After marking the margin of the lesion, the initial circumferential mucosal incision is performed. Afterward, the TA solution (2 mg/mL) is submucosally pre-injected using a knife with an injection feature to create a TA-filled water cushion required during the cESD. The submucosal dissection is then performed, accompanied by the injection of the TA solution until the lesion is completely removed. The minimum dosage of TA is 40 mg for each 3 cm of the longitudinal length of the circumferential mucosal defect. Two additional sessions of TA injections are undertaken on the 5th and 12th postoperative days using a 23-gauge, 4 mm needle (figure 2G,H and online supplemental video 1). To avoid injuring the muscularis propria, the needle is inserted shallowly into the submucosal layer of the wound starting from the anal-side wound margin. TA is then injected in aliquots of 1 mL (2 mg) at intervals of 1 cm (figure 1E and online supplemental video 1). If the muscle layer is partially exposed during the cESD procedure, TA injections are omitted in that specific area to prevent potential muscle damage. All patients were followed up with endoscopy at 3 months postoperatively, and additional endoscopy was performed whenever the patient complained of dysphagia with a score ≥ 2. Endoscopic balloon dilation (EBD) was performed as required when the patient demonstrated postoperative stricture which was defined as the presence of resistance to the passage of a standard 9.9 mm diameter endoscope or failure to pass it through a stenosed segment. The more details of the methods are shown in the online supplemental methods.
Supplementary video
Schematic diagram of the key steps in SSPS. (A) Mark the lesion margin and incise mucosa circumferentially. (B) Submucosally pre-inject TA (2 mg/mL) as the water cushion using a knife with an injection feature. (C) Submucosally dissect accompanied by repeated TA injection until complete removal of the lesion. (D) A circumferential mucosal defect with TA retention. (E) Two additional TA injections on days 5 and 12 postoperatively.
The application of SSPS in a real-life case receiving cESD (case 2). (A) The endoscopy with NBI showed a superficial oesophageal cancer that involved the entire oesophageal circumference. (B) Initial circumferential mucosal incision was performed on both oral and anal sides after submucosal methylene blue (0.01 mg/mL) injection. (C) TA solution (2 mg/mL) pre-injection into the submucosal layer on the oral side using the Dual Knife J to form a TA-filled water cushion, then dissection. (D) Repeated submucosal TA injection and dissection until the lesion was completely removed. (E) Circumferential mucosal defect with white TA retention. (F) Lugol’s staining of longitudinally cut, flattened specimen. (G–H) TA (2 mg/mL) solution injection using a needle on days 5 (G) and 12 (H) postoperatively. (I) Complete wound healing without stricture by the 3- month endoscopy. cESD, circumferential endoscopic submucosal dissection; NBI, narrow band imaging; SSPS, submucosal steroid pre-injection strategy; TA, triamcinolone acetonide.
Between May 2023 and May 2024, nine patients were included in the final analysis with a mean follow-up time of 6 months (range: 3–12 months) (online supplemental figure S1 and S2). All patients successfully underwent SSPS. The clinicopathologic features and clinical outcomes are shown in table 1 and online supplemental table S2. No patients received additional endoscopy due to dysphagia. Complete wound healing was observed at the 3-month endoscopy after cESD in all patients (figure 2I, online supplemental video 1, online supplemental figure S3 D1, D3-D9). Post-cESD stricture occurred in one patient (11.1%, 1/9) with one session of EBD required in this patient. Among the other eight patients without stricture, one patient experienced dysphagia with a score of 1, and the remaining seven patients did not experience any dysphagia. No adverse events occurred in any patient.
Key information of the nine included patients
Discussion
Steroids are theoretically the optimal therapeutic agents to prevent oesophageal stricture following cESD because they can suppress the inflammatory response reducing collagen synthesis and fibroblast proliferation.6 7 However, the outcomes of previously reported steroid administration regimens in preventing post-cESD stricture were unfavourable1 2 8 (online supplemental table S1). In the present study, we attempted to apply SSPS for preventing post-cESD stricture based on the following considerations. In previous methods, steroids are typically administered after the cESD procedure when the inflammatory response at the wound site has already been initiated. This remedial type of steroid administration may have a limited role in suppressing the inflammatory response. The innovative concept behind SSPS is to establish an anti-inflammatory microenvironment throughout the entire cESD procedure by pre-injecting TA into the submucosal layer prior to lesion dissection and maintaining this microenvironment on the wound for approximately 20 days. Collagen synthesis and fibroblast proliferation can thus be suppressed from the beginning of the dissection thereby minimising the risk of oesophageal stricture. Furthermore, previously reported steroid injection methods have resulted in a punctate distribution of multiple steroid deposition sites in the submucosal layer of the wound.9 10 However, between these sites there are significant gaps that are not covered by steroids (online supplemental figure S4a). These gaps may also be a significant reason contributing to the ineffectiveness of these methods. In contrast, SSPS uses the TA solution to create a TA-filled submucosal water cushion required during the cESD procedure. This ensures the submucosal layer of the wound remains in constant exposure to TA throughout the entire cESD procedure. The wound has virtually no blind spots in terms of TA retention (online supplemental figure S4b). Additionally, within the theoretical framework of wound healing, the extended duration of steroid exposure is associated with reduced collagen synthesis and fibroblast proliferation. Hashimoto et al 8 10 previously described multiple sessions of local steroid injections on postoperative days 1 and 14 and postoperative days 3, 7 and 10, respectively, to prolong steroid retention. However, their strategies have shown little efficacy in preventing post-cESD stricture2 8 (online supplemental table S1). Currently, there is no optimal administration interval to prolong the duration of steroid exposure. Based on our endoscopic observation, we have found that the retention time of submucosal TA is approximately 5–7 days after local TA injection (online supplemental figure S5). Hence, we propose additional local steroid injections on postoperative days 5–7 and 12–14, which seems a reasonable approach to prolong steroid retention. This may be another significant reason that SSPS can effectively prevent post-cESD stricture.
Several specific technical points should be highlighted. First, we used the Dual Knife J (KD-655Q; Olympus, Tokyo, Japan) to administer submucosal TA injections during cESD to avoid injecting TA into the muscular or deeper layer using a needle, thereby minimising the risk of delayed perforation.11 12 However, the DualKnife J cannot achieve initial submucosal injection because it is only suitable for injection in the exposed submucosal layer. Therefore, we initially employed a puncture needle (NM-400L-0423; Olympus, Tokyo, Japan) for the initial submucosal injection before performing circumferential mucosal incision on both the oral and anal sides of the lesion. At this stage, the submucosal injection solution simply consisted of normal saline and methylene blue to avoid the risk of delayed perforation caused by injecting TA into the muscular or deeper layers. Once the circumferential incision was made, the submucosal layer became exposed, allowing subsequent TA injections into the submucosa with DualKnife J. Second, although there are no specific restrictions on the ESD procedures, the ‘double tunnel’ technique is commonly employed in our study. According to our experience, we have found that to achieve complete coverage of TA within each tunnel, a minimum of 10 mL of TA solution (2 mg/mL) is required per 3 cm along the tunnel. This implies that for every 3 cm of longitudinal length of the circumferential mucosal defect, a minimum of 20 mL of TA solution (2 mg/mL) is needed.
The concern regarding the adverse events associated with this strategy may primarily stem from the two additional post-cESD TA injections using a needle. Although this method is currently the most frequently employed for local steroid administration to prevent oesophageal post-ESD stricture, previous studies have shown that it carries potential risks, such as delayed perforation and oesophageal abscess.11 12 While none of our patients experienced any of these adverse effects, further exploration is also worth conducting on other local steroid administration methods that appear to present a lower risk, such as blunt injection or local swallowable budesonide.
While our strategy demonstrated promising results, this was a single-arm study with only a limited number of subjects. Further multicentre randomised controlled trials are necessary to establish its efficacy and safety. In conclusion, our results show that SSPS seems to be effective, safe and easy to perform in preventing oesophageal stricture following cESD.
Trial registration number
ChiCTR2400085095
Data availability statement
Data are available upon reasonable request. We will share the data on request.
Ethics statements
Patient consent for publication
Ethics approval
This study involves human participants and was approved by Medical Ethics Committee of Lanzhou University Second Hospital (2023A-812). Participants gave informed consent to participate in the study before taking part.
Supplementary materials
Supplementary Data
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Footnotes
KZ, PW, W-hL and YB are joint first authors.
Contributors Study concept and design: XY, KZ, PW, WL. Acquisition of data: XY, KZ, PW, WL, DC, LS. Analysis and interpretation of data: XY, KZ, YB, XN, MQ. Drafting the manuscript: All authors. Critical revision of the manuscript for important intellectual content: All authors. Statistical analysis: XY, KZ, YB, JD.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Provenance and peer review Not commissioned; internally peer reviewed.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.