Chinese patent medicine: Opening new perspectives for treatment of post-endoscopic submucosal dissection esophageal stricture in esophageal cancer patients

Abstract

Endoscopic submucosal dissection (ESD) is an effective technique for treating early esophageal cancer, and the prevention of postoperative esophageal stricture has emerged as a significant research topic. Zhou et al utilized an experimental minipig model to demonstrate that Kangfuxin (KFX) can improve postoperative esophageal stricture following ESD by inhibiting transforming growth factor-β1-driven fibrosis and the downstream fibrotic mediators Smad2/3. In this letter, we primarily discuss recent advancements in the treatment of esophageal stricture, the clinical applications of KFX, and the mechanisms involved in alleviating postoperative esophageal stricture, aiming to provide insights for advancing clinical practice and research in esophageal stricture after ESD.

Key Words: Post-endoscopic submucosal dissection; Esophageal stricture; Kangfuxin; Transforming growth factor-β1; Smad2/3

Core Tip: Post-endoscopic submucosal dissection esophageal stricture significantly affects patients' quality of life; however, current treatment options are inadequate to meet clinical demands. In this letter, we first examine the limitations of existing treatment methods for esophageal stricture. We then introduce the novel therapeutic agent Kangfuxin solution and elucidate its mechanisms of action. Finally, we explore some emerging treatment technologies and propose potential avenues for future research.

TO THE EDITOR

Esophageal cancer is one of the ten most prevalent cancers globally, and studying its treatment and prognosis is of paramount clinical importance. With advancements in endoscopic techniques, endoscopic submucosal dissection (ESD) has gradually supplanted endoscopic mucosal resection as a reliable method for treating early-stage esophageal cancer[1]. Compared to traditional methods, ESD is less invasive, allows for the complete resection of submucosal lesions larger than 2 cm, has a lower incidence of positive margins, offers higher accuracy in pathological diagnosis, and effectively identifies risk factors for lymph node metastasis, thereby reducing recurrence rates[2,3]. However, ESD presents greater technical challenges, requires longer operational times, and carries a heightened risk of adverse events, including bleeding, perforation, and esophageal stricture[4].

TREATMENT OF ESOPHAGEAL STRICTURE

Current research has identified that resecting more than three-quarters of the circumferential esophageal mucosa during ESD is a significant risk factor for the development of esophageal stricture[5]. The esophagus's unique dual-layered muscular structure, comprising an inner circular layer and an outer longitudinal layer, contributes to the high incidence of strictures following esophageal injury. Recent studies suggest that esophageal strictures may originate from structural damage to the esophageal epithelial barrier, which subsequently triggers chronic inflammation and excessive activation of the transforming growth factor (TGF)-β signaling pathway[6]. This process promotes the transformation of fibroblasts into myofibroblasts[7], leading to excessive fibrosis at the wound site and resulting in stricture formation[8]. In clinical practice, common interventions to prevent esophageal strictures include endoscopic balloon dilatation (EBD) and temporary stent placement. While EBD is widely utilized, the need for repeated procedures increases the risk of complications such as esophageal perforation and mediastinitis[9]. Although stent therapy can be effective, it is associated with the risk of stent migration.

In contrast, pharmacological treatments offer the advantage of avoiding such limitations associated with physical interventions. Corticosteroids are the primary pharmacological approach for managing esophageal stricture, typically administered through preoperative oral routes and/or postoperative local injections. However, the efficacy of corticosteroids varies depending on the severity of the patient's condition and individual response to the drug[10,11]. Furthermore, prolonged or frequent use of corticosteroids may lead to a range of adverse effects, including infections, immunosuppression, peptic ulcers, and osteoporosis[4]. Another pharmacological agent, mitomycin C (MMC), a chemotherapeutic agent known to inhibit fibrosis, has been shown to reduce the frequency of dilatation procedures when applied locally. However, the optimal dosage and potential side effects of MMC remain poorly defined[12].

Kangfuxin (KFX), an ethanol extract derived from the dried body of Periplaneta americana, has gained attention for its potential in treating esophageal stricture. Traditionally, KFX is administered orally for gastric pain, bleeding, and conditions such as gastric and duodenal ulcers, as well as ulcerative colitis. Externally, it is used to treat burns, scalds, fistulas, and pressure ulcers. Given KFX's broad pharmacological effects including anti-inflammatory, anti-infective, tissue repair promotion, and immune modulation, researchers have increasingly focused on its application for esophageal stricture. Recently, Zhou et al[13] published findings in the World Journal of Gastroenterology indicating that KFX could alleviate esophageal stricture following ESD. To enhance the reliability of their animal model, the authors selected experimental minipigs for complete circumferential esophageal ESD. After 21 days of KFX treatment post-surgery, a significant reduction in the severity of esophageal stricture was observed. Newly formed esophageal tissue exhibited characteristics more akin to normal tissue, including increased softness, enhanced tensile strength, and improved mucosal integrity. Furthermore, the authors explored the underlying molecular mechanisms and found that KFX inhibited the expression of ACTA2, fibronectin, and collagen I in a dose-dependent manner in vitro, thus reducing fibrosis and improving tissue repair. Moreover, KFX effectively suppressed TGF-β1-driven fibrosis and the downstream fibrotic molecules Smad2/3, preventing excessive activation of primary esophageal fibroblasts and fostering healing.

These findings present a safe and cost-effective approach for the treatment of post-ESD esophageal stricture and provide valuable insights into the underlying mechanisms. However, as the authors acknowledge, the study has limitations, including the absence of comparative data between direct application and oral administration of KFX, as well as limited methods for assessing esophageal stricture. To address these gaps, we propose an experimental design based on the work of Zhou et al[13] to compare the two administration methods. Experimental minipigs would be divided into three groups: (1) A control group; (2) A KFX topical application group; and (3) A KFX oral administration group. The initial dosage for both groups would be set at 0.74 mL/kg/day, consistent with the protocol used in Zhou et al’s study[13]. After 21 days of treatment, the effects of the two administration methods would be evaluated through dysphagia scoring, endoscopic examination, and measurement of biochemical markers, including TGF-β and ACTA2.

Additionally, KFX may modulate signaling pathways such as p38/nuclear factor kappa B[14], signal transducer and activator of transcription 3[15], autophagy[16], and apoptosis[17] and further research is warranted to explore their roles in context of post-ESD esophageal stricture. Investigating proteomic changes before and after treatment could help identify key molecular components involved in fibrosis and further clarify KFX's mechanisms of action, representing a potential direction for future studies. As an organic extract, the specific active components of KFX in treating post-ESD esophageal stricture, the optimal therapeutic concentration, its impact on postoperative recovery, and the potential side effects associated with long-term use remain unclear. Should KFX be considered for clinical use, further investigations into its adverse reactions and contraindications are crucial.

There remains substantial potential for improving the prevention and treatment of esophageal stricture. Consequently, researchers have developed a variety of innovative therapeutic strategies, including self-expanding metal stents, self-expanding plastic stents, autologous oral mucosal cell sheet transplantation[18], betulin gel[19], thigh skin grafts, oral administration of conditioned medium from mesenchymal stem cells[20], exosome therapy[21], and biodegradable esophageal stents. Among these, exosomes stand out due to their exceptional biocompatibility and targeted delivery capabilities, making them ideal candidates for drug delivery. When combined with the active components of KFX, exosomes could enhance anti-inflammatory and anti-fibrotic responses, thereby improving therapeutic efficacy. Moreover, drug-eluting stents, originally designed for coronary artery stenosis, incorporate a polymer drug layer that enables sustained drug release[22]. By combining KFX’s active components with biodegradable polymers and coating them onto the stent surface, it may be possible to optimize the release rate of KFX, thereby facilitating long-term delivery and promoting wound healing while reducing fibrosis. The ongoing development of these advanced techniques provides a diverse range of options for managing esophageal stricture. The integration of KFX with these emerging technologies may offer a promising strategy for the precise management of post-ESD esophageal stricture, potentially improving clinical outcomes for patients.

CONCLUSION

Advanced endoscopic techniques offer high precision, minimal invasiveness, and improved prognoses for patients with esophageal cancer; however, they are often associated with postoperative complications, such as esophageal stricture. Recent research by Zhou et al[13] has demonstrated that KFX can inhibit TGF-β1 and its downstream fibrosis-related molecules, Smad2/3, thereby preventing excessive fibrotic repair and mitigating esophageal stricture following ESD. As a commonly used formulation of Chinese patent medicine that can be administered both orally and topically, KFX exhibits promising clinical applications. Nevertheless, its complex composition and the specific active components responsible for its therapeutic effects remain incompletely understood. Further clinical studies are necessary to determine the optimal administration route and dosage for effectively treating esophageal stricture. The development of new technologies is expanding the therapeutic options available for esophageal stricture, and the combined use of KFX with these innovative techniques or other effective medications may provide a reliable strategy to enhance patient management. Such advancements have the potential to significantly improve the quality of life for patients post-ESD and contribute to the evolution of clinical treatment strategies.