Abstract
Background
In patients with unresectable malignant biliary obstruction, brachytherapy combined with self-expandable metal stents (SEMS) has demonstrated extended stent patency and survival. However, researches rarely evaluate the outcomes of brachytherapy combined with subsequent systemic therapy, and most obstruction sites are located in the hilar bile ducts. The extrahepatic biliary tract lacks intrinsic structural support, limiting the application of locoregional therapies and predisposing to rapid clinical deterioration if drainage is delayed. The purpose of this study is to investigate the utility of SEMS combined with 125I brachytherapy in the treatment of unresectable malignant distal biliary obstruction (MDBO), providing evidence to guide locoregional management of this patient population.
Methods
This study retrospectively enrolled 187 patients first diagnosed with unresectable MDBO undergoing SEMS treatment at our center between August 2020 and July 2024. The brachytherapy group simultaneously received iodine-125 seed implantation (53 patients), while the control group received only SEMS placement (134 patients). We collected comprehensive clinicopathological data, including demographics, tumor characteristics, hepatic function, Eastern Cooperative Oncology Group (ECOG) performance status, and subsequent anticancer therapies. The study endpoints included overall survival and stent patency time. The duration of patency and overall survival was calculated using the Kaplan-Meier method, and the risk factors were assessed using the Cox proportional hazards models.
Results
The stent patency in the brachytherapy group was significantly longer than that in the control group [275 and 168 days, hazard ratio (HR) =0.50, 95% confidence interval (CI): 0.29–0.88, P=0.01]. The overall survival in the brachytherapy group was significantly longer than that in the control group (208 and 152 days, HR =0.60, 95% CI: 0.39–0.93, P=0.02). Furthermore, the combination of brachytherapy and subsequent systemic therapy significantly improved both stent patency (P=0.02) and overall survival (P=0.001) compared to monotherapy.
Conclusions
125I brachytherapy appears more effective than stent placement alone in regard to stent dysfunction and survival in this MDBO cohort. Moreover, 125I brachytherapy followed by subsequent systemic therapy is associated with further extensions in patient survival and stent patency.
Keywords: Brachytherapy, iodine-125, malignant biliary obstruction, jaundice, self-expandable metal stent (SEMS)
Highlight box.
Key findings
• Self-expandable metal stents (SEMS) plus 125I brachytherapy significantly prolongs stent patency and overall survival versus stent alone in unresectable malignant distal biliary obstruction (MDBO). Both brachytherapy and systemic treatment are independent protective factors for prognosis.
What is known and what is new?
• SEMS plus 125I brachytherapy benefits malignant biliary obstruction, but data on MDBO and synergy with systemic therapy are limited.
• Brachytherapy combined with SEMS offers advantages in patients with MDBO and has a synergistic effect with systemic therapy.
What is the implication, and what should change now?
• “SEMS + brachytherapy + systemic therapy” should be considered as a multimodal treatment strategy for MDBO.
Introduction
Malignant distal biliary obstruction (MDBO), caused by many malignancies such as bile duct cancer, pancreatic cancer, or metastatic tumor (1,2), results in biliary strictures in the distal half of the extrahepatic bile duct (3). Approximately 80% of cases of malignant biliary obstruction are already missing the chance for surgery at the time of first diagnosis (4). Percutaneous transhepatic biliary stenting (PTBS) is a reliable alternative treatment for unresectable MDBO (5-7). However, the incidence of recurrent biliary obstruction after the placement of self-expandable metal stents (SEMS) ranges from 19.8% to 50.0%, significantly impacting survival benefits (8-12). Biliary stents are prone to recurrent obstruction due to tumor ingrowth, stent migration, and sludge formation, which severely affects patient survival (13). Current studies have attempted to prolong stent patency through brachytherapy, drug-eluting stents, improved stent manufacturing and other approaches (14-16).
Previous studies have proven the efficacy of iodine-125 (125I) brachytherapy for various malignant tumors (17-19). Several studies concluded that combined SEMS and 125I seed implantation can enhance stent patency and improve overall survival in patients with malignant biliary obstruction (5,20,21). However, existing research mainly focused on hilar bile duct obstruction, and there have been few efforts to analyze the outcomes of combining brachytherapy with systemic therapy. Moreover, the causes of stent dysfunction in MDBO differ from those in hilar obstruction, and because the extrahepatic biliary tract lacks structural support, some locoregional therapies are limited in application (22). Therefore, exploring combination therapies and evaluating stent patency and survival in MDBO patients hold clinical significance. The purpose of this study is to further evaluate the efficacy and safety of SEMS combined with 125I brachytherapy for the treatment of unresectable MDBO. We present this article in accordance with the STROBE reporting checklist (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2026-0669/rc).
Methods
Patients
The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Institutional Review Board (IRB) of Institutional Review Board of Sun Yat-sen University Cancer Center (approval No. SL-B2025-092-01) and individual consent for this retrospective analysis was waived. We performed a comprehensive data review and analyzed the data of 391 consecutive patients diagnosed with unresectable malignant biliary obstruction, who were admitted to our institution from August 1, 2020 to July 31, 2024.
Inclusion criteria: (I) the diagnosis of unresectable MDBO was independently validated by two attending hepatobiliary surgeons, based on serological markers, histopathological evidence, and imaging findings; (II) serum total bilirubin (TBIL) level >34.2 μmol/L before intervention; (III) received percutaneous transhepatic biliary stenting; (IV) Eastern Cooperative Oncology Group (ECOG) performance status score ≤2.
Exclusion criteria: (I) intrahepatic or hilar biliary obstruction; (II) history of biliary stenting or bile duct surgery; (III) incomplete medical records or loss of follow-up; (IV) non-procedural causes of death within 7 days (Figure 1).
Figure 1.
Patient flow diagram.
Data collection and follow-up
Patient data were extracted from electronic medical records. The dataset included demographic characteristics [age, sex, Eastern Cooperative Oncology Group (ECOG) performance status]; tumor-specific variables (primary histology, baseline length of stricture, subsequent systemic anti-tumor therapy); procedural records (stent type, procedural-related complications); laboratory test results, and radiological findings. All patients were monitored through regular outpatient visits and telephone interviews until the end of the study or the time of death.
Definitions
Technical success was established as the accurate deployment of the biliary stent across the stricture, with cholangiography revealed unobstructed contrast medium flowing through the previously occluded segment and into the intestinal tract. Clinical success was established as serum TBIL levels returned to normal or decreased by more than 50% from preoperative baseline levels within two weeks following the procedure. Stent patency time was defined as the interval from stent deployment to dysfunction. For patients without stent dysfunction, the patency duration was censored at the time of the last follow-up or death. Overall survival was calculated from the date of the procedure to the date of death or the study cutoff. In alignment with the Society of Interventional Radiology (SIR) classification, severe complications were characterized as events resulting in mortality or significant morbidity, such as uncontrollable biliary sepsis, massive hemorrhage (biliary or intestinal), or acute renal failure; all other adverse events were classified as minor.
125I seed strand and biliary stent placement technique
Laboratory tests including routine blood count, biochemical examination, and coagulation function were conducted for all patients. In addition, a retrospective analysis of preoperative imaging [computed tomography (CT) or magnetic resonance imaging (MRI)] was performed to assess anatomical features and tumor burden, thereby facilitating the selection of the most appropriate percutaneous approach. The quantity of 125I seeds for implantation was calculated based on the preoperative computerized treatment planning system. Each 125I seed (Larvin Bioengineering Technology Co., Ltd.) has an outer diameter of 0.08 mm, a length of 4.45 mm, an effective radiation radius of 1.7 cm, a radioactivity of 0.8 mCi, and a half-life of 59.6 days. Arranged the seeds in a straight line using a 4F catheter. Pinch both ends of the catheter to ensure they match the length of the seed string, thereby preventing leakage. The heated vascular clamps were used to seal both ends of the catheter. The deployment of the stent and 125I seed strand was performed under strict aseptic conditions by interventional radiologists with over five years of experience, utilizing ultrasound and fluoroscopic guidance. A percutaneous approach was used to target and dilate the peripheral intrahepatic bile ducts using a 22-G Chiba needle (Cook, Bloomington, IN, USA). Subsequently, a Neff percutaneous catheterization system was introduced, and cholangiography was performed through the outer sheath to visualize the location and extent of the stricture. Then, a 0.035-inch guidewire was navigated across obstruction, followed by advancement of the outer cannula over the wire to traverse the stenotic segment. With the guidewire exchanged out, the seed string was guided through the sheath to the designated location. Next, the outer sheath was removed, and the stiff guidewire was passed through the treatment segment and reinserted into the distal duodenum. Subsequently, a SEMS was deployed across the stricture. Stent dimensions (8 mm in diameter; 40–80 mm in length) should be selected to ensure that the coverage extends at least 10 mm beyond the narrow proximal and distal edges. The seed strand was secured between the expanded stent and the bile duct wall. The specific type of stent is determined by consensus between two interventional radiologists, each with more than 10 years of experience, based on the patient’s clinical characteristics and anatomical concerns. Final stent placement and patency were confirmed by repeat cholangiography (Figures 2,3). Finally, an 8.5Fr external biliary drainage catheter (Cook Medical) was temporarily placed in all patients to facilitate bile drainage and decrease the incidence of infection and bleeding. The decision to remove the drainage catheter was evaluated based on the postoperative reduction in serum total bilirubin levels or the findings of follow-up cholangiography after 1–2 weeks. All data were carefully recorded, and patients were monitored for immediate complications such as bleeding, infection, or bile leakage.
Figure 2.
A 41-year-old man with distal common bile duct cholangiocarcinoma who underwent placement of a SEMS combined with an intraluminal 125I seed strand. (A) Percutaneous transhepatic cholangiography demonstrated a stricture localized to the common bile duct. (B) Cholangiography confirming adequate expansion of the deployed SEMS, with the 125I seed strand optimally apposed between the expanded stent and the biliary wall. (C) Dose distribution of 125I seed strand on TPS. (D) Three-dimensional reconstructed dose distribution of the 125I seed strand. (E) DVH of the 125I seed strand calculated post-implantation via the TPS. DVH, dose-volume histogram; SEMS, self-expandable metal stent; TPS, treatment planning system.
Figure 3.
Flowchart of percutaneous transhepatic SEMS combined with 125I seed strand placement. SEMS, self-expandable metal stent; TPS, treatment planning system.
Assessments and follow-up
All patients underwent laboratory tests within 2–4 weeks after the interventional procedure. From the second month onward, laboratory tests and telephone follow-ups were conducted monthly. If the TBIL levels exceeded 85.5 μmol/L, with or without symptoms of cholangitis (e.g. abdominal pain, recurrent fever ≥38 ℃, or leukocytosis >10.0×109/L), contrast enhanced CT, magnetic resonance cholangiopancreatography (MRCP), or cholangiography were performed to confirm stent dysfunction. In cases exhibiting radiologically confirmed stent dysfunction, salvage interventions such as stent revision or external biliary drainage were contemplated. In light of the diversity of primary malignancies among enrolled patients, all systemic therapy regimens were selected per tumor-specific guidelines and finalized via multidisciplinary team (MDT) discussions involving medical oncologists, interventional radiologists, hepatobiliary surgeons, and supportive care specialists, with comprehensive consideration of individual patient factors including ECOG performance status, hepatic function, and preexisting comorbidities, to ensure compliance with standard-of-care protocols.
Statistical analysis
The Shapiro-Wilk test was utilized to judge the distribution pattern of continuous variables. Descriptive statistics for normally distributed data were reported as the mean ± standard deviation and compared using the independent samples t-test; conversely, non-normally distributed variables were summarized as the median (interquartile range) and analyzed via the Mann-Whitney U test. Categorical variables were presented as frequencies and percentages, with group comparisons conducted using either the chi-square test or Fisher’s exact test. Cumulative stent patency and overall survival were analyzed by the Kaplan-Meier method with the log-rank test. If the cumulative patency curves crossed, the Breslow test was used for analysis. To identify factors influencing stent patency and survival, univariate Cox proportional hazards regression was performed. Variables achieving a P value <0.1 in the univariate analysis were subsequently entered into a multivariate Cox regression model, employing a stepwise selection procedure based on the likelihood ratio test, to determine independent predictors. The P<0.1 preselection threshold reduces the risk of missing clinically relevant covariates in our limited-sample cohort, while the LR test ensures more stable model fit assessments than Wald or score tests. Statistical significance was defined as a two-sided P value <0.05. All analyses were executed using IBM SPSS Statistics for Windows, Version 26.0 (IBM Corp.) and R software, Version 4.2.2 (R Foundation for Statistical Computing).
Results
Patient characteristics
Two hundred and thirty-eight patients were excluded from the study: hilar biliary obstruction (n=122); history of biliary stenting or bile tract surgery (n=60); incomplete medical records or loss of follow-up (n=21); non-procedural causes of death within 7 days (n=1). Ultimately, a total of 187 patients with unresectable MDBO who underwent PTBS were enrolled. Among them, 53 patients received adjuvant intraluminal 125I seed brachytherapy in conjunction with stent placement (brachytherapy group), whereas the remaining 134 patients were managed with stenting alone (control group) (Figure 1). The average age was 59.0 years (range, 52.0–67.0 years), with 136 males and 51 females. The leading cause of obstruction was bile duct cancer (48.1%), followed by metastatic nodes (37.4%), pancreatic cancer (8.6%), and hepatocellular carcinoma (5.9%) (Table 1).
Table 1. Patient characteristics.
| Characteristics | All (n=187) | Brachytherapy group (n=53) | Control group (n=134) | P value |
|---|---|---|---|---|
| Age (years) | 59.0 [52.0–67.0] | 60.0 [55.0–68.0] | 58.5 [49.0–66.0] | 0.09 |
| Sex | 0.59 | |||
| Female | 51 (27.3) | 13 (24.5) | 38 (28.4) | |
| Male | 136 (72.7) | 40 (75.5) | 96 (71.6) | |
| Etiology | 0.10 | |||
| HCC | 11 (5.9) | 3 (5.7) | 8 (6.0) | |
| Bile duct cancer | 90 (48.1) | 33 (62.3) | 57 (42.5) | |
| Pancreatic cancer | 16 (8.6) | 3 (5.7) | 13 (9.7) | |
| Metastatic lymph nodes | 70 (37.4) | 14 (26.4) | 56 (41.8) | |
| ECOG status | 0.73 | |||
| 1 | 60 (32.1) | 18 (34.0) | 42 (31.3) | |
| 2 | 127 (67.9) | 35 (66.0) | 92 (68.7) | |
| Child-Pugh score | 0.62 | |||
| ≤7 | 97 (51.9) | 29 (54.7) | 68 (50.7) | |
| >7 | 90 (48.1) | 24 (45.3) | 66 (49.3) | |
| Stent type | 0.15 | |||
| Uncovered | 134 (71.7) | 34 (64.2) | 100 (74.6) | |
| Covered | 53 (34.6) | 19 (35.8) | 34 (25.4) | |
| Length of stricture (cm) | 3.2 [2.8–3.8] | 3.2 [2.8–3.7] | 3.2 [2.8–3.8] | 0.81 |
| Laboratory parameters | ||||
| WBC (×109/L) | 7.8 [5.4–10.3] | 7.4 [5.1–10.0] | 7.9 [5.7–10.4] | 0.42 |
| TBIL (μmol/L) | 232.9 [134.1–378.5] | 227.2 [112.9–437.6] | 234.5 [145.5–346.5] | 0.93 |
| ALT (U/L) | 69.2 [45.2–116.9] | 68.3 [41.7–107.5] | 70.2 [46.6–124.8] | 0.35 |
| AST (U/L) | 87.4 [58.5–128.4] | 69.4 [43.9–111.3] | 97.4 [60.1–141.3] | 0.001 |
| ALP (U/L) | 387.3 [256.9–658.2] | 358.3 [212.3–543.3] | 399.6 [279.2–681.4] | 0.13 |
| GGT (U/L) | 334.0 [189.7–718.6] | 310.7 [189.4–634.2] | 353.3 [189.5–722.9] | 0.51 |
Data are n, n (%) or median [interquartile range]. ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, gamma-glutamyltransferase; HCC, hepatocellular carcinoma; TBIL, total bilirubin; WBC, white blood cell.
Efficacy and safety
All patients in both groups achieved technical success (100%). The liver biochemical parameters were significantly improved from the preoperative period to 2 weeks postoperatively (all P<0.05) (Table 2). Clinical success was achieved in 81.1% and 68.7% of patients in the brachytherapy and control groups, respectively, with no significant difference (P=0.08). Subsequent systemic therapy was initiated in some patients after the liver function was improved, 25 (47.2%) patients in the brachytherapy group and 82 (61.2%) patients in the control group, with no significant difference (P=0.08). No major procedure-related complications occurred in either group. Thirty-two cases had minor complications (17.1%) in two groups, including 10 cases of cholangitis (5.3%), 4 cases of pancreatitis (2.1%), 5 cases of self-limiting hemorrhage (2.7%), and 13 cases of abdominal pain (7.0%). There was no significant difference in the incidence of complications between the two groups (P=0.33). All complications could be well controlled by conservative symptomatic treatment (Table 3).
Table 2. Liver function parameters before and 2 weeks after the procedure.
| Variables | Brachytherapy group (n=53) | Control group (n=134) | P value | ||||||
|---|---|---|---|---|---|---|---|---|---|
| Before | After | Decline rate (%) | P value | Before | After | Decline rate (%) | P value | ||
| TBIL (μmol/L) | 227.2 (112.9–437.6) | 53.5 (30.0–90.7) | 75.7 (59.8–81.2) | <0.001 | 203.8 (137.1–295.4) | 59.7 (30.7–121.8) | 71.6 (35.6–82.4) | <0.001 | 0.19 |
| ALT (U/L) | 68.3 (41.7–107.5) | 46.4 (31.7–60.1) | 37.7 (8.5–27.7) | 0.001 | 87.1 (45.8–152.0) | 40.1 (21.3–66.6) | 50.0 (–11.9 to 70.3) | <0.001 | 0.17 |
| AST (U/L) | 69.4 (43.9–111.3) | 45.2 (28.3–60.6) | 36.2 (3.1–57.2) | <0.001 | 106.4 (60.9–151.6) | 52.9 (32.9–92.9) | 39.6 (–14.4 to 66.3) | <0.001 | 0.66 |
| ALP (U/L) | 358.3 (212.3–543.3) | 202.5 (153.7–329.2) | 42.0 (9.3–63.7) | <0.001 | 363.7 (223.7–491.1) | 220.7 (155.0–344.9) | 46.0 (18.5–64.1) | <0.001 | 0.48 |
| GGT (U/L) | 310.7 (189.4–634.2) | 128.0 (91.0–264.8) | 51.4 (25.4–69.8) | <0.001 | 391.3 (179.9–752.5) | 167.7 (95.8–282.9) | 53.9 (0.4–74.6) | <0.001 | 0.85 |
Data are median [interquartile range]. ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; ECOG, Eastern Cooperative Oncology Group; GGT, gamma-glutamyltransferase; TBIL, total bilirubin.
Table 3. Clinical outcomes.
| Clinical outcomes | Brachytherapy group (n=53), n (%) | Control group (n=134), n (%) | P value |
|---|---|---|---|
| Stent dysfunction | 0.27 | ||
| No | 37 (69.8) | 82 (61.2) | |
| Yes | 16 (30.2) | 52 (38.8) | |
| Clinical evaluation | 0.08 | ||
| Poor reduction of jaundice | 10 (18.9) | 42 (31.3) | |
| Clinical success | 43 (81.1) | 92 (68.7) | |
| Subsequent systemic anti-tumor therapy | 0.08 | ||
| No | 28 (52.8) | 52 (38.8) | |
| Yes | 25 (47.2) | 82 (61.2) | |
| Procedural-related complications | 0.33 | ||
| Cholangitis | 4 (7.5) | 6 (4.5) | |
| Pancreatitis | 1 (1.9) | 3 (2.2) | |
| Self-limited hemobilia | 2 (3.8) | 3 (2.2) | |
| Abdominal pain | 5 (9.4) | 8 (6.0) | |
Long-term stent patency and survival
The median stent patency was significantly higher in the brachytherapy group [275.0 days, 95% confidence interval (CI): 238.3–311.7] than that of control group (168.0 days, 95% CI: 103.6–232.4) [hazard ratio (HR) =0.50, 95% CI: 0.29–0.88, P=0.01]. Meanwhile, the overall survival was significantly higher in the brachytherapy group (208.0 days, 95% CI: 141.5–274.5) than that of control group (152.0 days, 95% CI: 123.5–180.5) (HR =0.60, 95% CI: 0.39–0.93, P=0.02) (Figure 4).
Figure 4.
Kaplan-Meier analysis of the stent patency time (A) and overall survival (B) for brachytherapy and control group.
To further explore the efficacy of brachytherapy combined with systemic anti-tumor therapy in MDBO, we conducted a subgroup investigation (Figure 5). Among the population, 25 patients received combined brachytherapy and systemic anti-tumor therapy (combined group), 28 patients underwent brachytherapy, and 82 patients underwent systemic anti-tumor therapy. Median stent patency time was better in the combined group (P=0.02) (Figure 5A). Moreover, the overall survival was also significantly higher in the combined group (P=0.001) (Figure 5B).
Figure 5.
Kaplan-Meier analysis comparing stent patency time (A) and overall survival (B) for combination group and monotherapy group.
Prognostic factors
The results of prognostic factors for stent patency and survival are summarized in Tables 4,5. We incorporated relevant clinical and therapeutic factors potentially influencing prognosis for analysis. We found that placement of covered stents (HR =0.478, P=0.03), combined with brachytherapy (HR =0.430, P=0.004) and received systemic anti-tumor therapy (HR =0.449, P=0.001) were protective factors for stent patency. Meanwhile, combined with brachytherapy (HR =0.575, P=0.01) and received systemic anti-tumor therapy (HR =0.671, P=0.049) were protective factors for overall survival.
Table 4. Univariate and multivariate analysis of prognostic factors of patency time in patients with malignant distal biliary obstruction (n=187).
| Variables | Univariate analysis | Multivariate analysis | ||||
|---|---|---|---|---|---|---|
| HR | 95% CI | P value | HR | 95% CI | P value | |
| Sex | ||||||
| Female | Reference | – | – | – | – | – |
| Male | 1.268 | 0.713–2.257 | 0.41 | – | – | – |
| Age | 0.989 | 0.965–1.012 | 0.33 | – | – | – |
| Stent type | ||||||
| Uncovered | Reference | – | – | Reference | – | – |
| Covered | 0.487 | 0.248–0.957 | 0.03† | 0.478 | 0.243–0.943 | 0.03‡ |
| Etiology | ||||||
| Metastatic nodes | Reference | – | – | – | – | – |
| HCC | 1.144 | 0.551–2.375 | 0.71 | – | – | – |
| Bile duct cancer | 0.654 | 0.373–1.148 | 0.13 | – | – | – |
| Pancreatic cancer | 0.447 | 0.138–1.450 | 0.18 | – | – | – |
| Child-Pugh score | ||||||
| ≤7 | Reference | – | – | – | – | – |
| >7 | 1.002 | 0.550–1.438 | 0.63 | – | – | – |
| Cholangitis prior to stent placement | ||||||
| No | Reference | – | – | – | – | – |
| Yes | 1.107 | 0.637–1.922 | 0.71 | – | – | – |
| TBIL before stent placement | 1.000 | 0.998–1.001 | 0.95 | – | – | – |
| TBIL decline rate at 2 weeks after stent placement | 0.545 | 0.368–0.807 | 0.002† | 0.688 | 0.411–1.151 | 0.15 |
| Length of stricture | 0.883 | 0.737–1.425 | 0.88 | – | – | – |
| Subsequent systemic anti-tumor therapy | ||||||
| No | Reference | – | – | Reference | – | – |
| Yes | 0.474 | 0.292–0.769 | 0.002† | 0.449 | 0.276–0.730 | 0.001‡ |
| Combination with brachytherapy | ||||||
| No | Reference | – | – | Reference | – | – |
| Yes | 0.503 | 0.286–0.883 | 0.01† | 0.430 | 0.243–0.762 | 0.004‡ |
| Procedural-related complications | ||||||
| No | Reference | – | – | – | – | – |
| Yes | 1.052 | 0.551–2.011 | 0.87 | – | – | – |
| ECOG score | ||||||
| 1 | Reference | – | – | – | – | – |
| 2 | 0.907 | 0.548–1.501 | 0.70 | – | – | – |
†, variables with P values <0.1 in the univariate analysis were included in the multivariate Cox regression analysis using the stepwise method (likelihood ratio); ‡, P value ≤0.05 was considered to indicate statistical significance. CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; HCC, hepatocellular carcinoma; HR, hazard ratio; TBIL, total bilirubin.
Table 5. Univariate and multivariate analysis of prognostic factors of overall survival in patients with malignant distal biliary obstruction (n=187).
| Variables | Univariate analysis | Multivariate analysis | ||||
|---|---|---|---|---|---|---|
| HR | 95% CI | P value | HR | 95% CI | P value | |
| Sex | ||||||
| Female | Reference | – | – | – | – | – |
| Male | 0.784 | 0.515–1.195 | 0.25 | – | – | – |
| Age | 0.992 | 0.976–1.008 | 0.33 | – | – | – |
| Stent type | ||||||
| Uncovered | Reference | – | – | – | – | – |
| Covered | 0.796 | 0.498–1.271 | 0.33 | – | – | – |
| Etiology | ||||||
| Metastatic nodes | Reference | – | – | – | – | – |
| HCC | 1.355 | 0.726–2.527 | 0.34 | – | – | – |
| Bile duct cancer | 1.170 | 0.753–1.818 | 0.48 | – | – | – |
| Pancreatic cancer | 1.002 | 0.469–2.140 | 0.99 | – | – | – |
| Child-Pugh score | ||||||
| ≤7 | Reference | – | – | – | – | – |
| >7 | 1.081 | 0.730–1.601 | 0.697 | – | – | – |
| Cholangitis prior to stent placement | ||||||
| No | Reference | – | – | Reference | – | – |
| Yes | 1.491 | 0.975–2.279 | 0.06† | 1.400 | 0.914–2.144 | 0.12 |
| TBIL before stent placement | 1.000 | 0.999–1.001 | 0.91 | – | – | – |
| TBIL decline rate at 2 weeks after stent placement | 0.790 | 0.522–1.194 | 0.26 | – | – | – |
| Length of stricture | 1.058 | 0.805–1.391 | 0.68 | – | – | – |
| Subsequent systemic anti-tumor therapy | ||||||
| No | Reference | – | – | Reference | – | – |
| Yes | 0.710 | 0.478–1.056 | 0.09† | 0.671 | 0.450–0.999 | 0.049‡ |
| Combination with brachytherapy | ||||||
| No | Reference | – | – | Reference | – | – |
| Yes | 0.601 | 0.389–0.928 | 0.02† | 0.575 | 0.371–0.890 | 0.013‡ |
| Procedural-related complications | ||||||
| No | Reference | – | – | – | – | – |
| Yes | 1.330 | 0.813–2.177 | 0.25 | – | – | – |
| ECOG score | ||||||
| 1 | Reference | – | – | – | – | – |
| 2 | 0.860 | 0.569–1.301 | 0.47 | – | – | – |
†, variables with P values <0.1 in the univariate analysis were included in the multivariate Cox regression analysis using the stepwise method (likelihood ratio); ‡, P value ≤0.05 was considered to indicate statistical significance. CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; HCC, hepatocellular carcinoma; HR, hazard ratio; TBIL, total bilirubin.
Discussion
Currently, limited data focused on the efficacy of combined 125I brachytherapy and subsequent systemic therapy for unresectable MDBO. For obstruction located in the extrahepatic bile ducts, direct implantation of 125I seeds into tumors is challenging due to typically short diameter tumor and the lack of safe and reliable percutaneous access. Thus, ablation techniques and intratumoral 125I seed implantation have limited applicability. In such cases, it is important to evaluate the efficacy of intraluminal brachytherapy, and its combination with systemic chemotherapy may offer potential survival benefits. Our results suggest that the integration of 125I brachytherapy with SEMS effectively sustains stent patency and augments survival in MDBO. Notably, patients underwent the combination regimen of 125I brachytherapy and systemic anti-tumor therapy exhibited markedly prolonged stent patency and superior survival outcomes relative to those receiving monotherapy.
Patients with unresectable MDBO typically require PTBS to alleviate jaundice and improve liver function (23). While providing mechanical relief, the stent itself exerts no oncological control. Tumor ingrowth through the stent mesh frequently occurs, compromising stent patency and precipitating the return of jaundice [6]. The uncovered SEMS are easier to deploy due to their open mesh design, which helps reduce sludge accumulation and bacterial colonization. However, they are more susceptible to tumor invasion (24). In contrast, covered CEMS prevents tumor growth into the stent by blocking it with a membrane, but the ends of the stent remain susceptible to blockage due to excessive tumor growth (7). Iodine-125 seeds as a continuous low-dose-rate radiation source can trigger apoptosis in tumor cells by directly damaging DNA structures (25). 125I brachytherapy has been proven to inhibit the growth of various tumors and induce tumor regression, thereby addressing the limitation of SEMS in lacking antitumor efficacy. Brachytherapy offers advantages over other local treatments because it can be planned and implemented concurrently with percutaneous stent placement, which is the first step in treating malignant biliary obstruction. This makes it a more attractive therapeutic option.
Xu et al. found that intraluminal brachytherapy combined with stenting conducted superior outcomes to stent alone, with significant improvements in both stent patency and median survival (26). Taggar et al. indicated that brachytherapy combined with biliary stent placement is a profitable tool for the treatment of malignant obstruction and can significantly improve the prognosis (20). A prospective clinical study comparing brachytherapy stents with traditional metal stents found that the insertion of brachytherapy stents improved stent patency and enhanced overall survival rates (5). Their cases mostly involved obstructions at the hilar bile ducts. In this cohort with distal biliary obstruction, combination with 125I brachytherapy significantly prolonged both stent patency and overall survival compared to stenting alone. Furthermore, multivariate analysis identified that receiving 125I brachytherapy and subsequent systemic therapy are both favorable prognostic factors for stent patency and survival. These results demonstrate the benefits of brachytherapy for patients with MDBO.
Some reports suggest combination chemotherapy protects against metal stent dysfunction (27,28). Chi and Ji et al. revealed that 125I seed strands combined with subsequent chemotherapy significantly enhanced survival in pancreatic head cancer patients with malignant biliary stricture (29,30). In our subgroup analysis, we found that the combination of brachytherapy and subsequent systemic therapy significantly improved both stent patency (P=0.02) and overall survival (P=0.001) compared to monotherapy. Owing to the limited therapeutic radius of 125I brachytherapy, intraluminal seeding often proves insufficient for eradicating more distant extraductal tumor burden. Systemic therapy can compensate for this limitation of 125I brachytherapy, and their combination significantly enhances antitumor efficacy. Additionally, in a subset of our patients who received only brachytherapy without systemic antitumor therapy, the results showed that their survival period was not significantly different from that of patients who received systemic antitumor therapy alone. We found that patients receiving brachytherapy alone had better survival within 180 days after surgery. Beyond this period, the efficacy may decline due to reduced radioactivity of 125I seeds after three half-lives. For patients with relatively localized lesions, continuous brachytherapy might be sufficient to control tumor progression effectively.
In our study, brachytherapy demonstrated non-inferior efficacy in normalizing liver function compared to stent placement alone. These results suggest that 125I brachytherapy does not adversely affect liver function in MDBO patients. As corroborated by Reniers et al. (31) and Chino et al. (32), the effective radiation radius of 125I confines its effects primarily to the tumor region, causing minimal injury to healthy tissues and organs in the surrounding area. This further supports that intraluminal brachytherapy is a safe approach for MDBO.
This study highlights the potential application of brachytherapy combined with systemic therapy for MDBO patients. However, this research remains some limitations. First, potential biases may exist during data extraction and analysis due to the retrospective approach. In addition, there was unavoidable selection bias in how patients were assigned to the treatment groups. Second, due to interference from metal stents, accurately assessing local tumor regression is challenging. Third, the variety of systemic treatment regimens made it difficult to conduct further subgroup analyses. Due to the uncontrollable immortal time bias, the independent effect of subsequent systemic therapy may be unreliable. Finally, because many patients never develop stent dysfunction until their death, the assessment of stent patency duration may be inaccurate. Significant prospective controlled studies are needed in the future to further investigate the survival benefits and impact on stent patency of brachytherapy for MDBO patients.
Conclusions
In summary, 125I brachytherapy significantly superior to stent alone in reducing stent occlusion and prolonging survival. When 125I brachytherapy followed with subsequent systemic therapy, it further enhances survival outcomes. Therefore, 125I brachytherapy may be considered a preferable technique for MDBO.
Supplementary
The article’s supplementary files as
Acknowledgments
None.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Institutional Review Board (IRB) of Institutional Review Board of Sun Yat-sen University Cancer Center (approval No. SL-B2025-092-01) and individual consent for this retrospective analysis was waived.
Footnotes
Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2026-0669/rc
Funding: None.
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2026-0669/coif). The authors have no conflicts of interest to declare.
Data Sharing Statement
Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2026-0669/dss
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