Cholangiocarcinoma (CCA) is a malignant tumor that occurs in the epithelial cells of the bile duct, with the second-degree bile duct used as an anatomical marker (1). Intrahepatic cholangiocarcinoma is located at the proximal segment of the secondary bile duct, while extrahepatic cholangiocarcinoma (eCCA) is found from the primary bile duct to the bile-pancreatic ampulla. eCCA encompasses perihilar cholangiocarcinoma (pCCA) and distal cholangiocarcinoma (dCCA). pCCA arises from the principle bile duct to the confluence of the hepatic duct and cystic duct, whereas dCCA extends from the cystic duct to the bile-pancreatic ampulla (2).

eCCA mainly manifests with bile duct obstruction, for which radical surgical resection is still the only curative means (3, 4). The 5-year survival rates of pCCA and dCCA patients after radical surgical resection are 20%–30% and 18%–43%, respectively (5–8). For eCCA patients who are inoperative, unwilling to undergo surgery, or who are in poor systemic condition and cannot tolerate surgery, the palliative treatment is mainly biliary drainage, which includes external biliary drainage and internal biliary drainage. The internal biliary drainage are in line with physiology to avoid body fluid loss (9).

The implantation of self-expandable metallic stent (SEMS) is the main means of bile-enteral drainage. However, the stent itself cannot stop tumor growth, and more than 50% of SEMSs are reblocked after 6 months due to tumor overgrowth, leading to rehospitalization and re-intervention and greatly reducing patients' quality of life (10–12). How to inhibit tumor growth, prolong the patency time of patients with biliary stents and overall survival (OS) and improve the quality of life of patients are major clinical problems at present.

¹²⁵I particles are a low-energy radiation source, with the persistent emission of low-energy gamma rays capable of inducing damage to the DNA double strands of tumor cells (13, 14). This process effectively eradicates tumor cells across various stages of cell division, inhibits tumor proliferation, and facilitates apoptosis. The effective radiation radius of ¹²⁵I particles is 1.7 cm, which delivers a high dose to tumor tissues and causes low damage to surrounding tissues (15); therefore, they have been widely used to treat malignant tumors. Especially, ¹²⁵I particles are widely used in solid tumors, such as liver cancer, prostate cancer, lung cancer, and pancreatic cancer, and have achieved good efficacy (16–19). In recent years, researchers have applied radioactive stents combined with ¹²⁵I seeds in the treatment of eCCA. However, studies of ¹²⁵I seed implantation combined with biliary stenting in patients with extrahepatic BDT are relatively rare and heterogeneous (20, 21).

Therefore, in this study, we aimed to conduct a retrospective analysis to evaluate the potential enhancement in efficacy of biliary stenting when used in conjunction with ¹²⁵I particles.

Self-expandable metal stent is a common choice for enteral drainage in eCCA patients, but its effectiveness is not satisfactory. In this study, we included 40 patients in the control group who underwent biliary stent implantation and 40 patients in the ¹²⁵I group who underwent biliary stent implantation combined with ¹²⁵I particles implantation. The results confirmed that, compared with the control group, the ¹²⁵I group had significantly improved postoperative liver function, relieved symptoms of obstructive jaundice, reduced tumor marker levels, and prolonged stent patency time and OS without serious complications.

The most common symptom of eCCA is obstructive jaundice, and biliary drainage is an indispensable treatment technique for unresectable eCCA patients with obstructive jaundice. Endoscopic biliary stent placement was introduced in the 1980s; owing to its minimal invasiveness and practicability, it is now the preferred procedure for the palliative treatment of most eCCA patients. Although there are various types of stents, metal stents are recommended for unresectable cases because they have longer patency time than plastic stents do. In recent years, chemotherapy, immunotherapy and other methods prolong the survival of patients (22). However, a new difficulty arises: the bile duct will still be blocked again, and the patient will experience a recurrence of jaundice in a short period of time, which seriously affects the survival and quality of life of the patient (23).

Stent re-occlusion fundamentally arises from a cascade effect of tumor activity, foreign body reaction, and bile flow dysregulation. Neoplastic cells progressively invade the lumen through longitudinal overgrowth at stent margins or transverse ingrowth through stent interstices. Concurrently, the stent itself induces chronic inflammation and fibroblast activation, driving granulomatous hyperplasia and collagen-deposition stenosis. These processes collectively cause bile stagnation, promoting supersaturation and precipitation of bilirubin/cholesterol into sludge matrices that entrap calcium salts and bacterial biofilms, ultimately forming obstructive calcium bilirubinate stones. This self-reinforcing cycle, wherein obstruction exacerbates sludge formation, sludge accumulation accelerates infection and hyperplasia, and hyperplastic tissue further constricts the lumen, demands integrated therapeutic strategies targeting all pathological axes simultaneously. It is precisely this multidimensional challenge that makes biliary stenting combined with radioactive seed implantation a rational solution: the stent restores immediate drainage patency while the radionuclide's localized irradiation concurrently suppresses tumor proliferation, mitigates inflammatory hyperplasia, and delays sludge formation through continuous biological modulation (24, 25).

At present, ¹²⁵I particles have been confirmed to be effective and safe in the treatment of portal vein tumor thrombi (26, 27). Because eCCA is discovered in the advanced stage and clinical cases are rare, the application of ¹²⁵I seed implantation combined with biliary stenting in advanced eCCA is rare at home and abroad, the research directions are new, and there is currently no unified treatment guidelines. On the basis of the above studies combined with our previous clinical observations, we speculated that biliary stent with brachytherapy of ¹²⁵I seed implantation may result in better treatment outcomes for patients with eCCA and provide a standardized treatment option for patients with advanced eCCA.

In this study, we collected the clinical data of 80 patients with advanced eCCA combined with obstructive jaundice. The results showed both groups effectively reduced obstructive jaundice, improved liver function, and reduced postoperative tumor marker levels in the short term. However, over time, in the stent alone group, tumor growth again caused lumen stenosis or blockage; the stent patency rates at 3 and 6 months after operation were 92.5% and 67.5%, respectively. Additionally, there was a rapid increase in ALT, AST, and bilirubin. In contrast, in the biliary stent combined with ¹²⁵I seed implantation group, because ¹²⁵I can perform long-term and low-dose radiation on tumor tissues, stent patency can be maintained for a longer time. The stent patency rates at 3 and 6 months, respectively, were 97.5%, 90%. Moreover, the ALT, AST, and bilirubin levels at 3 and 6 months were significantly lower than those in the biliary stent alone group, showing a gradual upward trend. The same situation was also observed for postoperative tumor marker levels. These advantages led to longer survival in the biliary stent combined with ¹²⁵I seed implantation group, with a median survival of 15 months, which was significantly greater than that of the biliary stent alone group (9 months). With respect to the long-term efficacy of treatment for advanced eCCA, the implantation of a biliary stent combined with ¹²⁵I seeds was superior to internal biliary stent implantation alone. Although more postoperative complications were observed in the biliary stent with ¹²⁵I seed implantation group, the main complications were gastrointestinal symptoms (nausea, vomiting, etc.), which were relieved within a short time after operation and did not have a significant impact on patient's life.

This study has several limitations. Especially, our study was limited to a single-center, retrospective study, but the baseline levels of the included two groups of patients were not different, which makes up for this limitation to a certain extent.

In summary, the therapeutic efficacy of biliary stenting combined with ¹²⁵I particles implantation for the treatment of advanced eCCA is superior to that of stenting alone. This combined approach effectively relieves biliary obstruction, facilitates the restoration of liver function, and extends both biliary tract patency and patient survival duration. Therefore, the integration of biliary stenting with 125I particle implantation represents a highly promising strategy for patients with advanced eCCA.