The efficacy and safety of ¹²⁵I seeds combined with biliary stent placement versus stent placement alone for malignant biliary obstruction: a systematic review and meta-analysis

Introduction

Malignant biliary obstruction (MBO), characterized by stenosis and blockage of extrahepatic or intrahepatic bile ducts, is a common clinical disease primarily caused by various cancers including cholangiocarcinoma, pancreatic cancer, gallbladder cancer, and cancer metastasis (1-3). Due to the silent and occult clinical manifestations, MBO patients are always diagnosed at the advanced stage when painless obstructive jaundice develops (4,5). By this time, most patients have bypassed the optimal treatment period and cannot benefit from radical resection due to extensive tumor growth (5). About 70% of MBO cases are unresectable, resulting in poor quality of life and low survival for most MBO patients (3). During the recent 3 decades, surgeons and interventional therapists have endeavored to alleviate patients’ clinical symptoms and correct complications by means of conventional or minimally invasive approaches (6,7). Palliative treatment of stent implantation is one of the common therapeutic methods for MBO, which has been widely accepted and used for decades (8).

A high recurrence rate has been found in patients implanted with non-therapeutic stents (9-12). On the one hand, because the stent itself has no therapeutic effect on the tumor, stent occlusion can be caused by the growth of tumor tissue into the lumen through the stent mesh. On the other hand, stent occlusion can be caused by epithelial hyperplasia, biofilm deposition, biliary sludge, and granulation tissue formation over the duration of stent placement (13). Compared to the stent placement alone, Iodine-125 (¹²⁵I) seeds combined with biliary stent placement can effectively reduce the stent occlusion rate because the ¹²⁵I seeds can inhibit the tumor growth (14). The suggestion that permanently radioactive seed implantation can be used to treat MBO was made by several scholars in the early 1900s. ¹²⁵I, a persistent radiation material, is a preferred material for particle scaffolds due to its function of directly injuring the DNA double helix to inhibit the replication of tumor cells and inducing apoptosis (15). Efforts have been made to introduce irradiation stents loaded with ¹²⁵I seeds in China and various types of biliary stents with special structure and materials have been designed for MBO treatment by percutaneous transhepatic cholangiography (PTC) or endoscopic retrograde cholangiopancreatography (ERCP) (8).

Recently, animal experiments, cohort studies, and randomized controlled trials (RCTs) on the treatment of MBO patients with particle stents have been published successively, and the finding that ¹²⁵I seed implantation can improve the prognosis of patients has been confirmed by meta-analysis (16,17). However, the participants included in these population studies were mostly mixed populations, including patients with MBO caused by various cancers such as cholangiocarcinoma, gallbladder cancer, pancreatic cancer, gastric cancer, colorectal cancer, and primary liver cancer. Currently, it is unknown whether ¹²⁵I stent implantation has the same therapeutic effect on patients with MBO caused by different cancers, and 2 published meta-analyses have failed to clarify the issue. Therefore, we performed this meta-analysis, aiming to verify the efficacy and safety of ¹²⁵I implantation for MBO patients, and to further explore the differences in the efficacy and safety of seed implantation among different patients through subgroup analysis. We present this article in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting checklist (available at https://qims.amegroups.com/article/view/10.21037/qims-22-824/rc).

Methods

Eligibility criteria

Databases such as PubMed, Wiley Online Library, Cochrane library, Google Scholar, the Web of Science, China National Knowledge Infrastructure (CNKI), VIP, and Wanfang were screened for related articles published from inception to October 30, 2022. The following keywords were used: ¹²⁵I seeds stent OR iodine seeds stent OR iodine-125 seeds OR biliary stenting combined with iodine-125 seed AND malignant biliary obstruction OR malignant biliary stricture OR malignant bile duct obstruction OR malignant obstructive jaundice OR malignant extrahepatic biliary obstruction. The articles were selected by 2 independent reviewers by reviewing the title and abstract of each study. In addition, references cited in systematic review reports on the same or a similar topic were also screened for relating articles. Articles were not subjected to language or geographical limitations, but were required to meet the following inclusion criteria: (I) RCT or cohort study on MBO caused by unresectable tumor (distal or proximal); (II) Patients in the treatment group received stent combined with ¹²⁵I particle treatment, whereas patients in the control group received stent monotherapy (only metal stent implantation); (III) single and multi-center studies; (IV) both endoscopic and percutaneous approaches for stent implantation. The exclusion criteria were as follows: (I) no information on patient survival time or survival rate was provided; (II) patients received other radiotherapy; (III) single-arm study; (IV) no baseline patient information such as age and gender were provided, or the baseline information between the 2 groups was not balanced; (V) animal experiments, narrative reviews, and conference abstracts. Any disagreements between the 2 reviewers in the above process were resolved by a third reviewer. The study was not registered on a specific platform.

Data collection

Two authors independently extracted the following information to a database established by Microsoft Excel 2016 software (Microsoft Corp., Redmond, WA, USA): (I) basic information of each article, such as author’s name, year and type of publication, and country; (II) patient characteristics and treatment information; and (III) information on efficacy and adverse reactions. We extracted the number of events and the total number for dichotomous variables and the means and standard deviations for continuous variables.

Quality appraisal

The Newcastle-Ottawa Scale (NOS) was used to evaluate the quality of articles (18,19). NOS, which is one of the commonly used quality evaluation methods in prospective studies, evaluates the quality of the study from 9 aspects including the selection of the study population, the comparability between groups, and the measurement of results. The total score is 9 points, and articles scoring 7–9 points were considered high-quality articles. For randomized trials, the Cochrane risk of bias tool (Cochrane Collaboration, Copenhagen, Denmark) was also used to assess potential bias risk. Any disagreement was discussed with a third author to reach a consensus.

Definition of outcome

The primary endpoint was survival, which was defined as the interval between initial treatment and death or the end of the study. Secondary outcomes included complication, stent occlusion, and biochemical response within 1 week. Complication-related indicators included pancreatitis, cholecystitis, cholangitis, and hemobilia. Stent patency referred to the recurrence of biliary obstruction after stent placement. Stent patency time was defined as the time from stent placement to recurrence of biliary obstruction or the end of study. Biochemical indicators within 1 week included alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL), and direct bilirubin (DBIL).

Statistical analysis

Risk ratios (RRs) with 95% confidence intervals (CIs) were chosen to measure the effects of ¹²⁵I seed implantation for stent patency, patient survival, and complications, and weighted mean differences (WMDs) to measure the stent patency time, patient survival time, and laboratory values. All comparisons were performed by Stata software version 15.0 (StataCorp. LLC, College Station, TX, USA). The I² test and Q test were used to estimate the heterogeneity among the studies. A P value for Cochrane’s χ²<0.05 or I²>50% indicated that there was a high heterogeneity between the studies, and a random effects model was selected for the meta-analysis; otherwise, a fixed effects model was used. Sensitivity analysis was performed using the leave-one-out method to evaluate the robustness of the final result. Egger’s test was used to assess publication bias. Subgroup analysis and meta-regression were used to explore the differences in the results of different study populations and different study designs.

Results

Search results

A total of 4,059 articles were identified by the database research (Table S1), and 35 articles were identified by the previous systemic reviews. After removing 720 duplicates, 3,374 articles were assessed. A further 3,335 articles were excluded because the titles and abstracts were not relevant to the research purpose. Among the remaining 39 articles, 27 studies were excluded due to violations of the inclusion and exclusion criteria. Finally, 12 studies were included for meta-analysis. The specific screening process was shown in Figure 1. The 12 eligible studies included 4 English (14,20-22) articles and 8 Chinese articles (23-30), and the detailed information is shown in Table 1 and Table S2. All articles were single center studies conducted within China, with a quality score of 7–9 (Tables S3,S4). Of the 12 studies (Table S5), 2 included patients with MBO caused by hilar cholangiocarcinoma (cholangiocarcinoma group) (23,28), 5 included patients with MBO caused by unresectable hilar cancers (MHBO group; including cholangiocarcinoma, gallbladder cancer, liver cancer, etc.) (20,24,25,27,29), and the remaining 5 included patients with MBO of unlimited etiology (MMBO group) (14,21,22,26,30). Except for 3 RCTs (14,21,22), the remaining 9 articles were prospective cohort studies.

Figure 1 Flow chart of study inclusion.

A total of 679 patients were enrolled, among whom 329 received ¹²⁵I stent implantation (¹²⁵I group) and 350 received only stent implantation (control group). There were 204 males and 146 females in the ¹²⁵I group, and 180 males and 149 females in the control group. The baseline information, such as age and gender, was balanced and comparable between the 2 groups.

Death risk

A total of 310 patients died in the control group and 253 died in the ¹²⁵I group. The death risk in the ¹²⁵I group was 0.441 times (95% CI: 0.315 to 0.619, P<0.001) lower than in the control group, indicating that ¹²⁵I seed implantation reduced the mortality rate of MBO patients (Figure 2A and Table 2). Fixed effects models were adopted for meta-analyses since no significant heterogeneity was observed (χ²_Q=1.67, P_Q=0.998; I²=0%). The sensitivity analysis (Table 2) showed that the final result was robust. Subgroup analysis (Figure 2B) suggested that ¹²⁵I seed implantations reduced the death risk by 0.322 times (95% CI: 0.129 to 0.805, P=0.015; P_Q=0.856, I²=0%) in cholangiocarcinoma patients, 0.443 times (95% CI: 0.207 to 0.948, P=0.036; P_Q=0.938, I²=0%) in MHBO patients, and 0.482 times (95% CI: 0.320 to 0.726, P<0.001; P_Q=0.980, I²=0%) in MMBO patients. Meta-regression verified that the impact of seed implantation on death risk in MHBO patients (β=−13.00, 95% CI: −72.86 to 46.86, P=0.630) and MMBO patients (β=24.00, 95% CI: −37.96 to 85.96, P=0.398) was not different from than that in cholangiocarcinoma patients. Subgroup analysis and meta-regression also demonstrated that the death risk (Figure S1) calculated by RCTs (RR =0.349, 95% CI: 0.105 to 1.157, P=0.085; P=0.998, I²=0%) and calculated by prospective studies (RR =0.453, 95% CI: 0.318 to 0.644, P<0.001; P=0.897, I²=0%) was also not statistically different (β=−10.29, 95% CI: −62.68 to 42.10, P=0.667). Egger’s test (β=15.69, P=0.826) and the funnel plot (Figure S2) indicated that no potential publication biases were present.

Figure 2 Comparison of death risk between 125I groups and control groups. (A) Meta-analysis; (B) subgroup analysis by study population. RR, risk ratio; CI, confidence interval; W, weight; MBO, malignant biliary obstruction; MMBO, mixed MBO patients caused by various tumors; MHBO, patients with malignant hilar biliary obstruction.

Totals of 9 and 7 articles reported the mean survival time and median survival time, respectively. The pooled WMD of mean survival time between 2 groups was 3.310 months (95% CI: 2.848 to 3.771, P<0.001) and the median survival time was 3.458 months (95% CI: 2.658 to 4.259, P<0.001), suggesting that ¹²⁵I seed implantations increased the survival time compared with control groups (Figure S3 and Table S6). Random effects models were used due to high heterogeneity (mean survival: I²=87.4%, P_Q<0.001; median survival: I²=95.9%, P_Q<0.001). However, the results of sensitivity analysis (Table S6) showed that the final result was robust. Egger’s test (mean survival: β=6.036, P=0.067; median survival: β=3.286, P=0.544) indicated that no potential publication biases were present.

Complication risk

A total of 11 articles documented the occurrence of postoperative complications, including 333 patients in the control group and 326 patients in the ¹²⁵I group. Complications occurred in 45 patients in the control group and 50 patients in the ¹²⁵I group. Meta-analysis showed that seed implantations did not increase the risk of postoperative complications (RR =1.024, 95% CI: 0.963 to 1.090, P=0.450; Figure 3). Fixed effects models were used to conduct analyses since no significant heterogeneity was detected (P_Q=0.640; I²=0%). Sensitivity analysis (Table 3) showed that the final result was robust. Subgroup analysis (Figure S4) and meta regression also indicated that the pooled complication risk was not significantly different in different study populations (cholangiocarcinoma vs. MHBO: β=0.06, 95% CI: −0.11 to 0.24, P=0.425; cholangiocarcinoma vs. MMBO: β=0.03, 95% CI: −0.08 to 0.14, P=0.555) and different study types (β=−0.01, 95% CI: −0.11 to 0.10, P=0.886). Egger’s test (β=0.339, P=0.472) and funnel plot (Figure S5) analysis indicated that no potential publication biases were present.

Figure 3 Comparison of complication risk between 125I groups and control groups. (A) Meta-analysis. (B) Subgroup analysis by population. RR, risk ratio; CI, confidence interval; W, weight; MBO, malignant biliary obstruction; MMBO, mixed MBO patients caused by various tumors; MHBO, patients with malignant hilar biliary obstruction.

Stent occlusion risk

The postoperative biliary stent patency rate was reported on 10 articles. Among the total of 222 patients included in the control group, 157 developed stent occlusion, and among the 289 patients included in the ¹²⁵I group, 101 developed stent occlusion. The stent occlusion risk in ¹²⁵I group was 0.534 times (95% CI: 0.433 to 0.658, P<0.001; Figure 4) lower than the control group. Fixed effects models were used due to acceptable heterogeneity (P_Q=0.057, I²=45.4%). The sensitivity analysis (Table 4) showed that the pooled stent occlusion risk was robust. Subgroup analysis (Figure S6) and meta regression manifested that the pooled stent occlusion risk was not significantly different in different study populations (cholangiocarcinoma vs. MHBO: β=0.05, 95% CI: −0.58 to 0.68, P=0.862; cholangiocarcinoma vs. MMBO: β=0.23, 95% CI: −0.54 to 0.99, P=0.504) and different study types (β=0.11, 95% CI: −0.42 to 0.65, P=0.641). Egger’s test (β=−0.656, P=0.195) and funnel plot (Figure S7) analysis indicated that no potential publication biases were present.

Figure 4 Comparison of stent occlusion risk between 125I groups and control groups. (A) Meta-analysis. (B) Subgroup analysis by population. RR, risk ratio; CI, confidence interval; W, weight; MBO, malignant biliary obstruction; MMBO, mixed MBO patients caused by various tumors; MHBO, patients with malignant hilar biliary obstruction.

Information of mean stent patency time was provided in 6 articles, 2 of which also reported median stent patency time. The WMD of mean survival time between 2 groups was 3.394 months (95% CI: 2.639 to 4.148, P<0.001) and median survival time was 3.174 months (95% CI: 2.785 to 3.562, P<0.001), suggesting that ¹²⁵I seeds implantations increased the stent patency time of MBO patients compared with control groups (Figure S4). The random effects model and fixed effects model were performed for meta-analysis of the mean patency time (I²=96.7%, P_Q<0.001) and median patency time (I²=7.1%, P_Q=0.299), respectively. However, sensitivity analysis (Table S7) showed that the pooled result of mean patency time was robust. According to the results of Egger’s test, no potential publication bias was present (β=1.949, P=0.824).

Biochemical response within 1 weeks

A total of 4 studies recorded ALT levels before and 1 week after surgery; 3 studies recorded AST levels; 7 studies recorded TBIL levels; and 5 studies recorded DBIL levels. All indicators were balanced and comparable before surgery (Figure S8A-S8D). Meta-analysis showed that the improvement of TBIL (WMD =−14.969, 95% CI: −28.670 to −1.267, P=0.032; P_Q=0.409, I²=2.1%; Figure S9A) and AST (WMD =−14.653, 95% CI: −23.246 to −6.060, P=0.001; P_Q=0.900, I²=0%; Figure S9D) levels in the ¹²⁵I group 1 week after operation was significantly better than that of the control group, but no differences were observed in DBIL (WMD =−7.064, 95% CI: −17.910 to 3.782. P=0.202; P_Q=0.834, I²=0%; Figure S10A) and ALT (WMD =−7.974, 95% CI: −22.920 to 6.972, P=0.296; P_Q=0.086, I²=54.5%; Figure S10C). Both the control group (Figure S11A-S11D and Table S7) and the ¹²⁵I group (Figure S12A-S12D and Table S8) showed improvement in all indicators 1 week after surgery. Sensitivity analysis showed that the final result of all indicators was robust and Egger’s test indicated that no potential publication biases were present (all P>0.05).

Discussion

MBO greatly reduces the quality of life of patients, increases patient mortality, and also incurs a heavy social economic burden (31,32). At present, local chemoradiotherapy in combination with stent drainage, which has the advantages of effectiveness and minimal invasiveness, is the first choice for treatment of MBO patients with unresectable tumors (33,34). Previous studies have demonstrated that this therapy could prolong patient survival and reduces the risk of recurrent stent occlusion compared with conventional therapy. On the basis of previous studies, through meta-analysis, the current study further confirmed that ¹²⁵I stent implantation can reduce the MBO patients’ death risk and extend the patency time on the condition without increasing the risk of complications.

Our findings further confirmed the results of 2 meta-analyses published in recent years. Abuduwaili et al. found that patients treated with irradiated stents had longer survival [hazard ratio (HR) =0.46, IV, random, 95% CI: 0.34 to 0.63, P<0.001; I²=0%) and stent patency rates (HR =0.45, IV, random, 95% CI: 0.25 to 0.80; P=0.007, I²=59%) than those treated with conventional SEMS (16). Similarly, Xiang et al. discovered that stent combined with ¹²⁵I seeds showed longer mean survival (MD =125 days; 95% CI: 91 to 159 days; P<0.001) compared with stent placement alone (17). The X-rays emitted by ¹²⁵I (effective radiation radius of 17–20 mm, half-life of 60 days) can be kept within the tumor area to inhibit tumor growth into the mesh of the stent by directly killing the tumor cells, while ensuring that the surrounding normal tissues and adjacent organs are not damaged, thereby improving the patient's liver function and working status (35-37). Cancer cells undergo a cumulative superposition of damage effects under continuous irradiation, which prolongs the cell cycle and increases the total radiation dose in the G2-M phase, thereby helping to improve the radiation sensitivity (38,39). Therefore, X-ray irradiated tumor cells can remain in the radiation-sensitive period, G2 and M phases, to ensure that the tumor cells can be killed to the greatest extent, thereby improving the survival time and stent patency of MBO patients.

In order to fill in the gaps identified in previous studies, subgroup analysis and meta-regression were further conducted in our study to explore the difference in the efficacy and safety of seed implantation for MBO patients caused by cholangiocarcinoma, hilar tumors, and various other tumors. The results indicated that the efficacy of seed implantation in patients with MBO caused by hilar tumors was not different from that in patients with MBO caused by various tumors, suggesting that ¹²⁵I seed implantation was suitable for all patients with tumor-induced MBO, and no difference was observed in its efficacy. The meta-regression found that the results observed in RCTs were no different to those observed in prospective studies. The study design of RCT controls the influence of confounding bias on the observation results through random grouping. The current study strictly included prospective studies that reported balanced and comparable baseline information to avoid the interference of confounding factors, which may be one of the reasons why it was not a source of heterogeneity in this study.

As we all know, particle radiation can interact with body cells, tissues, and body fluids, ionize atoms or molecules of the tissue, and directly destroy certain macromolecular structures of the body, such as protein molecules, ribonucleic acid molecular chains, and enzymes (40). Therefore, seed implantation therapy is often thought to be associated with a high complication rate. However, the current meta-analysis showed that ¹²⁵I seed implantation cannot increase the patients’ complications risk, which was consistent with the previous 2 studies, illustrating the safety of seed implantation. The complications involved in the candidate articles included severe pain, pancreatitis, biliary tract perforation, stent migration, hemobilia, and asymptomatic amylase increase, among others. A meta-analysis for each complication was not performed, because of the lower complication rate. Regarding laboratory indicators, our meta-analysis found that serum ALT, AST, DBIL, and TBIL levels were decreased 1 week after surgery, and ¹²⁵I stent implantation was more conducive to the improvement of AST and TBIL levels in 1 week after surgery, but the effect on ALT and DBIL levels was not significant. The observation was slightly different from the results of Abuduwaili et al., whose findings suggested that the seed implantation was not responsible for the decreased AST levels, compared to the control group (16). The difference may have been caused by the sample size. Abuduwaili et al. included only 2 studies with 54 cases, whereas our study included 3 studies with 108 cases.

In addition to further confirming the conclusions of previous studies, the current study found for the first time through subgroup analysis that the efficacy of seed implantation in patients with MBO caused by cholangiocarcinoma was no different from that of those with MBO caused by hilar tumors or various types of tumors. The included studies were all high-quality articles with a quality score of 7–9, which further guarantees the reliability of the research. In addition to advantages, this study has several limitations. First, according to the inclusion criteria, only 12 studies were included in the analysis, and the sample size (including 676 MBO patients) may be insufficient, which may hinder the applicability of this analysis. However, no significant publication bias was detected among the 12 studies. Second, the participants may not be sufficiently representative of the broader population. Since seed implantation therapy was only recently introduced in China, all the included articles were single-center studies conducted within China. Therefore, the efficacy and safety of seed implantation need to be further verified in other populations and other regions. Conversely, only a single-center study conducted within China would ensure that our research results were not affected by race and region. Third, high heterogeneity was observed in the survival and patency times reported by 12 studies, which may have been caused by the difference in follow-up time. Fortunately, the sensitivity analysis supported the robustness of the final results, indicating that our results were not affected by the heterogeneity. Fourth, since few patients with MBO caused by a single tumor were recruited in primary studies, the current study cannot further conduct a meta-analysis to explore the efficacy of ¹²⁵I therapy on patients with MBO caused by various tumors.

Conclusions

In conclusion, ¹²⁵I seed implantation treatment is a significantly superior MBO treatment method than stent placement alone, which can effectively prolong the survival of patients and reduce the death risk and stent occlusion risk. Further, it is a safe and tolerable method with comparable complication risk to stent placement alone. It may be a useful and promising therapy for MBO patients, and its efficacy and safety for MBO caused by hilar tumors are no different from those caused by various tumors. In future studies, ¹²⁵I seed implantation therapy should be verified in different populations and regions.

Acknowledgments

Funding: This work was supported by the National Natural Science Foundation of China (No. 81971716).

Footnote

Reporting Checklist: The authors have completed the PRISMA reporting checklist. Available at https://qims.amegroups.com/article/view/10.21037/qims-22-824/rc

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-22-824/coif). The authors have no conflicts of interest to declare.

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.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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