A Novel Brachytherapy Biliary Drainage Catheter Loaded With 125I Seeds in Patients With Malignant Obstructive Jaundice: Preliminary Results Versus Iodine-125 Seed Strands Placement

Background The placement of 125I seeds was a safe method for treating cholangiocarcinoma .The purpose of this study was to compare a novel brachytherapy biliary drainage catheter (BBDC) with an Iodine-125 ( 125 I) seed strand after self-expandable metallic stent(SEMs) implantation in terms of safety and ecacy, as treatments for patients with cholangiocarcinoma of malignant obstructive jaundice (MOJ). Methods From September 2016 to December 2018, We retrospectively enrolled patients with biliary stent implantation after receiving either BBDC loaded with 125 I seeds (double-strands irradiation group) or an 125 I seed strand treatment (single-strand irradiation group, control group). The outcomes were analyzed regarding the relief of obstructive jaundice, interventional-related complications, stent patency and survival time.


Background
Malignant obstructive jaundice (MOJ) usually results from biliary invasion or compression by cholangiocarcinoma, but less than 10-20% of the patients are eligible for radical operation [1,2]. The implantation of the Self-expandable metallic stent (SEMS) is the main palliative treatment for patients with MOJ. However, due to the stent's stimulation of the bile duct wall and the lack of therapeutic properties for the tumor, stent stenosis and granulation tissue proliferation occured in the progress of the disease will make more than 50% of patients have stent re-obstruction within 6 months [3,4]. Hence, stents with longer patency are required to improve the survival rates of patients with MOJ. Fortunately, In 2012, Zhu et al [5] reported a radioactive biliary stent loaded with 125 I seeds exhibited a signi cantly prolonged stent patency compared with conventional stents. In recent years, some investigators have used the combination of 125 I seeds strand and SEMs as a new therapeutic treatment for MOJ [6].
Although it is a safe treatment, the cumulative brachytherapy dose is relatively low and brous connective tissue in the bile duct could reduce local irradiation effect [7]. In order to eliminate these disadvantages, a novel brachytherapy biliary drainage catheter (BBDC) loaded with double 125 I seed strands was designed. Of note, the e cacy and complication of the treatment for MOJ have not been largely studied to our knowledge. The aim of this study is to compare the safety, complication and e cacy of BBDC loaded with 125 I seeds (double-strands irradiation group) and 125 I seed strand (singlestrand irradiation group, control group) after SEMs was implanted in the follow-up after the treatment.

Patients
In this retrospective study, the inclusion criterion of eligible patients were as follow : (a) aged between 43 and 80 years, (b) biliary obstruction caused by any adenocarcinoma with histological or cytological con rmation by biopsy or previous surgical procedures, (c) symptoms such as jaundice related to biliary obstruction, (d) Eastern Cooperative Oncology Group (ECOG) performance of 0-2, (e) Patients underwent computed tomography or magnetic resonance cholangiopancreatography (MRCP) to evaluate the extent of the biliary obstruction prior to stenting,(f) unresectability or refusal to be surgically treated, (g) willing and able to comply with the study procedures and provide written informed consent to participate in the study. The exclusion criteria were as follows: (a) main portal vein tumor thrombus; (b) severe coagulation defect; (c) refractory ascites; (d) intrahepatic metastasis that extensively involves both lobes of the liver; (f) an ECOG performance of 3-4.

Device
A Nitinol self-expendable stent ( Niti-S Biliary stent, taewoong, Seoul, Korea ), with a diameter of 10 mm and length of 5-6 cm was used to treat the stenosis within common bile duct. A novel brachytherapy biliary drainage catheter(BBDC). (Tuoren, Henan, China) (Fig. 1) .The 125 I seeds (Said Biopharmaceutical Co, Ltd. Tianjin, China) were con gured in a cylindrical brachytherapy source encapsulated by titanium.
The details could be found in the (supplementary information A).

Procedures
Prior to the procedure, the extent of the tumor and the anatomy of the bile duct were evaluated by enhanced abdominal CT and/or MRCP. All procedures were performed under local anesthesia (2% lidocaine) and dezocine intravenous injection (5 mg). Firstly, under digital subtraction angiography (DSA) guidance (Artis Zeego, Siemens, Germany or Shimadiu Digte2400, Japan), percutaneous transhepatic cholangiography (PTC, Cook Inc., Bloomington, IN, USA) was performed to visualize the location and degree of biliary obstruction. Brachytherapy biliary drainage catheter (BBDC)and Iodine-125 ( 125 I) seed strand in bile duct placement time (1-1.5 months). Analysis of biochemical and imaging examination after one month of interventional treatment .The details for the interventional treatment could be seen in the (supplementary information B) and (Fig. 2).

De nitions
The primary end points were the technical success, clinical success, and stent patency. The secondary end points were complications, patient survival, and pre-and post-operative changes in the biochemical indicators. Technical success was de ned as the deployment of the BBDC with favorable contrast ow through the stent at one month. Clinical success was de ned as a successful BBDC removal and a reduction in serum bilirubin by at least 75% of the pretreatment value within one month. Complications were classi ed according to the guidelines of the Society of Interventional Radiology Standards of Practice Committee [8]. Stent occlusion was de ned as biliary dilatation on CT or MRI, combined with the recurrence of symptoms of malignant obstruction and an increase in serum bilirubin (> 51.3 µmol/L). The stent patency period was de ned as the interval between stent placement and the development of stent occlusion.

Statistical analysis
Continuous variables were summarized as mean ± standard deviation (SD). The Wilcoxon Signed Rank test was used to compare the pre-and post-procedure indicators. The Fisher exact test was also used to compare postoperative complications between the two groups. Survival and stent patency time were calculated according to the Kaplan-Meier method, and a P-value of < 0.05 was considered statistically signi cant. The calculations were performed by the SPSS software (version 23.0, SPSS, Chicago, Illinois, USA).

Results
The baseline characteristics of the BBDC group and the control group are well balanced ( Table 1). The technical success rate in both groups was 100%. None of the 125 I seeds were lost during the delivery and deployment as well as in vivo implantation process. The median estimated radiation doses for the reference points of the BBDC group and the control group were 85.14 ± 4.72 Gy and 44.35 ± 3.55Gy (P<0.05), as calculated by computer TPS over one month and the total number of 125 I seeds embedded in the patients of both groups was 38.84 ± 2.45 and 18.86 ± 2.75, respectively (P<0.05)

Clinical Success
The hospital stay of the BBDC group and the control group was 12.53 ± 4.67 days and 11.45 ± 5.29 days, respectively(P>0.05).Except for one in control group died of severe gastrointestinal bleeding three weeks after the treatment, the levels of ALT, TBIL and DBIL in both group decreased signi cantly, and the condition improved considerablely as well (p < 0.05). The ALB levels in the both group were increased slightly within one week, while the ALB levels continued to increase following treatment in the both group(p < 0.001). (Fig. 3

Discussion
Malignant obstructive jaundice (MOJ) is usually caused by Cholangiocarcinoma [9]. Regrettably, it is often detected at an unresectable stages with a poor prognosis, and the long-term survival rates remain dismal [10]. SEMs is considered to be the preferred palliative therapy for unresectable patients [11,12]. However, doubt about the e cacy suggests that SEMs might not able to prevent excessive tumor growth [13]. Worth mentioning, the ingrowth of tumor or epithelial hyperplasia would cause further restenosis. As reported, 50% of stent restenosis occurred within 3-6 months after the treatment [4]. In addition, this therapy has shown no bene cial for prolonging survival time [14,15]. Therefore, chemo-radiations therapy is suggested to be the complementary treatment which can be used successively or synchronously to prolong the survival and stent patency. Compared with external irradiation, brachytherapy is a safe and effective palliative therapy, which can provide more effective treatment dose for tumor and reduce the impact on normal organs and tissues [16,17].
At present, a multicenter phase III clinical trial for the treatment of MOJ with radioactive stent and traditional metal stent has con rmed that inserting radioactive stent instead of uncovered SEMs could improve the patency and overall survival rate of patients with unresectable malignant biliary obstruction [18]. Unfortunately, there are two serious problems in the insertion of irradiation stents. First, 125 I seeds cannot be taken out if complications occur after the treatment. Second, the seeds cannot be replaced after the 125 I seeds dose was completely released. In order to extend the stent patency and overall survival rate, investigators have attempted various therapies to control the growth of biliary tumors such as intraluminal radiofrequency ablation, photodynamic therapy, intraluminal high-dose-rate 192Ir radiation and paclitaxel-drug-eluting stents for malignant biliary obstruction. In the eld of brachytherapy, Iodine-125 ( 125 I) seeds strand has been applied to the treatment of cholangiocarcinoma and portal vein tumor thrombosis with promising results [19,20,21]. Studies have further con rmed that intraluminal brachytherapy using a single 125 I seeds strand is a viable and safe palliative treatment pressed by SEMs implantation, which can be used to treat cholangiocarcinoma and improve stent patency [22,23].
Nevertheless, single-strand 125 I particles cannot solve the problem of eccentric dose distribution.
To overcome these technical limitations, a BBDC loaded with double 125 I strands was designed. This design achieves drainage and brachytherapy simultaneously. Double 125 I strands provide better dose distribution than a single strand. In addition, the catheter can be removed or replaced when brachytherapy-related complications occur, or the intraluminal brachytherapy terminates. This retrospective study demonstrated the safety and reliability of the BBDC in the palliative treatment of malignant biliary obstruction. The technical success rate (100%) and early complication rate 26.3% (5/19) were similar to the previous studies [24], which indicated that the three-lumen catheter would not increase the complications or reduce the success rate of clinical treatment.  [25,26]. This may be due to the SEMs combined with a novel BBDC (double-125I seed strands irradiation) to inhibit tumor growth and proliferation, which subsequently alleviate long-term obstructive jaundice, thereby improving patients' liver function and survival time. To date, there is no dedicated TPS for the 125 I seed strands, and the relationship between the calculated radioactivity concentration and dose of TPS remains unclear. Therefore, further research is needed to con rm if the received radioactive dose is su cient.
This study has several limitations. The sample size is relatively small, which reduces the statistical power of the conclusion, however some of the results have already achieved the statistical signi cance. Selection biases might be existing in terms of the size or length of the metal stents. Second, because it is di cult to assess the tumor response after the treatment using the RECIST criteria, the objective assessment of tumor suppression by ILBT. Third, radiation might happen to other people with closing contact of the patients may be in uenced. Since the dose of the radiation on the surface of the patient's skin after placement is not accurately measured, the exact radiation exposure to others remains unknown. However, prudent precautions have been taken to reduce the contact with others.

Conclusion
In summary, our preliminary study showed that the newly designed BBDC loaded with 125 I seeds provided both drainage and brachytherapy, and again demonstrated the technical feasibility and safety of BBDC for the treatment of malignant biliary obstruction. However, more prospective studies are needed to further elucidate its effectiveness in the treatment of malignant obstructive jaundice. Authors' contributions ZL participated in the collection and analysis of data, the writing of the manuscript and specimen collection. XZ participated in data collection and analysis. DJ and YHLparticipated in the data analysis and manuscript revision. XH, ZL and DJ participated in manuscript editing. ZL and DJ participated in the data collection. XH participated in the study conception and supervision, data analysis and manuscript editing. All authors read and approved the nal version of the manuscript.

Funding
Young and middle-aged health science and technology innovation talent project of Henan Province(YXKC2020037);The Provincial and ministerial youth project and the Henan Medical Science and Technology Public Relations Program (SB201902014).

Availability of data and materials
The relevant raw data from this study can be readily available upon request for non-commercial purposes per a request from the corresponding author.
Ethics approval and consent to participate All procedures performed in the studies involving human participants were in accordance with the ethical standards of the First Hospital a liated to Zhengzhou University and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Consent for publication
Not applicable.