The burden of gastrointestinal tumors is rapidly increasing worldwide and is associated with significant morbidity and mortality. Colorectal cancer ranks third in incidence and second in mortality worldwide, with esophageal cancer ranking as the eighth most diagnosed cancer [¹,²]. Endoscopic submucosal dissection (ESD) has gained increasing acceptance as a suitable approach for gastrointestinal cancers due to its low rate of local recurrence compared to endoscopic mucosal resection [³,⁴,⁵].

The submucosal injection is a critical step in ESD, as it forms a submucosal cushion fluid that facilitates the elevation and separation of the lesion from the muscularis propria. This enhances en bloc resection and decreases the risk of complications by creating a physical barrier protecting deep tissues [⁶,⁷,⁸]. The ideal submucosal injection solution should fulfill the following criteria: (1) Ensure an adequately thick submucosal fluid cushion; (2) it should be capable of long-term retention under the mucosa, minimizing the need for frequent submucosal injections; (3) It should be affordable, readily accessible, simple to store, and administer; (4) Minimizing the occurrence of adverse events during ESD, such as hemorrhage and perforation, and maintaining the integrity of excised specimens to ensure accurate pathological results [⁶]. Currently, sodium hyaluronate is one of the most common solutions used for ESD. However, it has been confirmed that it may stimulate tumor growth after ESD [⁹].

Mensa is a thiol compound commonly used as prophylaxis against some chemotherapy drugs to prevent hemorrhagic cystitis. Additionally, Mensa exhibits a mucolytic effect, which is utilized to facilitate sputum expectoration during respiratory distress. Due to its unique chemical property, Mesna can break down disulfide bonds that connect polypeptide chains, which soften connective tissue fibers between different anatomical planes. Several clinical surgical studies have shown that applying an aqueous solution of Mesna directly to the surgical area helped in smoother blunt dissection and led to shorter operation times, decreasing the risk of hemorrhage [¹⁰,¹¹,¹²,¹³,¹⁴].

Na alginate (SA) has excellent water retention and viscoelastic properties. It is used in clinical settings to treat peptic ulcers or as a hemostatic agent [¹⁵,¹⁶,¹⁷]. SA has been used in Japan for more than 60 years as a protective agent for the digestive mucosa, typically at a 5% concentration. This extensive use has established the efficacy and safety of SA [¹⁸]. In 2018, Japan approved 0.6% SA for use as a submucosal injection solution in ESD [¹⁹]. We conducted this meta-analysis to evaluate the feasibility and safety of Na alginate and Mesna before endoscopic submucosal dissection.

The high cost and potential tumorigenesis associated with sodium hyaluronate (SH) [²⁵,⁹], a widely used ESD submucosal injection solution, prompted the search for an alternative. In the early 2010s, Akagi et al. proposed Sodium alginate (SA) as a safe and effective submucosal injection solution. SA is a non-toxic natural polysaccharide polymer isolated from brown seaweed [²⁵]. In addition to its low cost, SA is known for its safety, having been used in the treatment of peptic ulcer disease due to its protective and hemostatic properties on the mucosal membrane [¹⁵]. Lastly, the viscosity of SA helps in achieving reliable submucosal lift [⁹]. An early clinical experience with 3% SA in ESD was reported on 11 patients with early gastric cancer. The overall endoscopic en bloc resection rate was 100%. No major complications occurred with no tumor recurrence after a mean follow-up of 28 months [²⁵]. Later, the formulation of SA was improved to 0.6% to enhance injectability and facilitate uniform mucosal elevation [²⁸].

A randomized controlled trial (RCT) compared the efficacy and safety of 0.6% SA to 0.4% SH in ESD for esophageal and gastric lesions. Efficacy was based on the en bloc complete resection rate in ESD and the formation and maintenance of mucosal elevation upon injection. SA was found to be non-inferior to SH. In addition, the mucosal resection time was similar between the two groups [¹⁹].

The primary utility of Mesna is to facilitate submucosal dissection by dissolving disulfide bonds, thereby softening the connective tissue fibers [³⁰]. This also allows for less or no electrosurgical dissection, theoretically reducing the risk of perforation. In a pilot study, chemically assisted ESD with submucosal injection of Mesna led to a 100% en-bloc resection rate with a mean operation time of 21.17 ± 11.6 minutes [³⁰]. Subsequently, a double-blind RCT comparing Mesna to saline submucosal injection in ESD for gastric cancer found no difference in submucosal dissection time between the two groups [³¹]. However, there were fewer time-consuming cases (more than 30 minutes) in the Mesna group (P=0.049). Additionally, the subjective difficulty of ESD was significantly lower in the Mesna group. Both groups had similar en-bloc resection rates (Mesna: 100%, Controls: 98.08%) and perforation rates (Mesna: 0%, Controls: 1.92%) [³¹].

As for the adverse events, we found that, in the aspect of perforation incidence, Na alginate was slightly safer than the standard used solution, sodium hyaluronate (1% in the Na alginate cases vs. 3% in the sodium hyaluronate in previous trials) [³²]. When we compared the incidence of delayed bleeding between sodium hyaluronate and Na alginate solutions, it was found that Na alginate (with a pooled incidence of 5% for both 0.4% and 0.6% concentrations) is not as safe as sodium hyaluronate (with a pooled incidence of 1%). However, if we compare the two concentrations of Na alginate, the concentration of (0.6% Na Alginate) is much safer than (0.4% Na Alginate) (adverse event rates are 2% and 22%, respectively). This detail should guide future studies to focus more on the safer (0.6%) concentration in trials, maximizing the benefits of the new solution while minimizing the risk of adverse events. Our study has some limitations. First, it includes a small number of single-arm studies without comparative ones. Additionally, there are some variations in results during subgroup analysis. This persistent heterogeneity is likely attributable to differences in endoscopist skill levels and procedural efficiency across centers rather than the intervention itself. Variations in technique, experience, and procedural protocols at different institutions inherently contribute to the observed discrepancies in procedure duration, making it a challenging factor to standardize across studies. Finally, all the studies are conducted in Asia with small sample sizes, which may limit the generalizability of our results. We suggest conducting randomized controlled trials to guide future directions, choices, and careful interpretation of results. Future enhancements should prioritize expanding network diversity, improving data validation mechanisms, and developing more sophisticated tools for bias mitigation.

Our study revealed that both Na alginate, especially Na alginate (0.6%), and Mesna are effective and safe alternatives to sodium hyaluronate for submucosal injection in endoscopic submucosal dissection. Na alginate (0.6%) achieved high en-bloc resection rates with notably low adverse event rates, making it a particularly promising option. Mesna also showed excellent en bloc resection rates and significantly reduced procedural times, highlighting its efficiency in ESD procedures. Both solutions offer cost-effective and safer options for clinical practice, addressing the limitations associated with sodium hyaluronate, such as high cost and potential tumorigenic risk. Future studies should focus on further validating these findings through larger randomized controlled trials and exploring the optimal concentrations and formulations for enhanced safety and efficacy.