Comment on UDCA prophylaxis after gastrectomy for gastric cancer

To the Editor, We read with great interest the randomized clinical trial evaluating the long-term efficacy of ursodeoxycholic acid (UDCA) for preventing gallstone formation after gastrectomy in patients with gastric cancer[1]. The authors reported that after 80 months of follow-up, gallstone formation occurred in 10.00% and 12.83% of patients receiving UDCA (300 mg and 600 mg, respectively), compared with 26.21% in the placebo group. These findings suggest that a 12-month course of UDCA may provide sustained protection against postoperative gallstone formation. The multicenter, randomized, double-blind design and long-term follow-up represent important strengths, and the study adds valuable evidence to the growing body of literature supporting pharmacologic prophylaxis in this setting. Previous randomized studies have similarly suggested that UDCA can reduce gallstone formation after gastrectomy[2]. Building upon these important findings, several areas may offer opportunities for further investigation that could enhance the mechanistic understanding and clinical implementation of UDCA prophylaxis. Artificial Intelligence announcement is in accordance with the TITAN guideline[3]. First, incorporating direct assessments of gallbladder motility in future studies may provide additional physiological insight. Impaired gallbladder contractility following gastrectomy – related to vagal denervation and altered gastrointestinal hormonal signaling – has been recognized as a major contributor to postoperative biliary stasis and gallstone formation[4]. Functional evaluations such as cholecystokinin-stimulated ultrasonography or hepatobiliary scintigraphy could therefore complement imaging-based gallstone detection. Such measurements may help clarify whether UDCA exerts its protective effect primarily through modification of bile composition or through additional influences on gallbladder motility and bile flow. Experimental studies suggesting that UDCA may improve gastrointestinal and biliary motility further support the potential value of integrating functional assessments in future investigations[5]. Second, the interaction between reconstruction method and UDCA efficacy may warrant closer examination. Patients in the study underwent several reconstruction techniques, including Billroth I, Billroth II, and Roux-en-Y reconstruction. These procedures differ in their effects on gastrointestinal physiology, vagal nerve integrity, and enterohepatic circulation of bile acids. Roux-en-Y reconstruction, in particular, has been associated with a higher risk of postoperative gallstone formation, possibly due to more pronounced alterations in biliary motility and bile flow dynamics[6,7]. Although reconstruction type was included as a covariate in the statistical model, future analyses exploring whether the magnitude of UDCA benefit varies across reconstruction techniques could provide clinically useful insights and support a more individualized approach to postoperative prophylaxis. Third, further characterization of gallstone composition could help refine the interpretation of prophylactic effects observed in this study. Gallstones occurring after gastrectomy may differ from those in the general population, with some studies suggesting a greater contribution of pigment stones related to biliary stasis and bacterial metabolism[8]. Because UDCA primarily reduces cholesterol supersaturation in bile and is most effective in preventing cholesterol stones, understanding the composition of newly formed gallstones may help clarify the mechanisms through which UDCA exerts its protective effect in postoperative gastric cancer patients[9]. Future studies incorporating gallstone compositional analysis or bile biochemical profiling may therefore provide valuable mechanistic context. Beyond these clinical considerations, the broader implementation of UDCA prophylaxis may also benefit from evaluation from a health-systems perspective. Although UDCA is generally well tolerated, routine prophylactic therapy inevitably raises questions regarding cost, medication adherence, and healthcare resource utilization. While the present trial demonstrates a clear reduction in gallstone formation, future studies incorporating health-economic modeling – such as cost-effectiveness or cost-utility analyses – could help determine whether universal prophylaxis or a risk-stratified strategy represents the most efficient approach for clinical practice. Evidence from bariatric surgery populations suggests that UDCA prophylaxis can reduce gallstone incidence, although the optimal implementation strategy continues to be explored[10]. In conclusion, this well-conducted randomized trial provides important evidence supporting UDCA prophylaxis for preventing gallstone formation after gastrectomy for gastric cancer. Future studies integrating functional assessments of gallbladder motility, reconstruction-specific analyses, characterization of gallstone composition, and health-economic evaluation may further advance the understanding and optimal application of UDCA prophylaxis in postoperative gastric cancer patients.