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ORIGINAL ARTICLE
Year : 2020  |  Volume : 16  |  Issue : 2  |  Page : 286-291

A newly designed biliary brachytherapy drainage catheter for patients with malignant biliary obstruction: A pilot study


Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China

Date of Submission26-Sep-2019
Date of Decision12-Nov-2019
Date of Acceptance06-Apr-2020
Date of Web Publication28-May-2020

Correspondence Address:
Jianzhuang Ren
Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052
China
Xinwei Han
Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.JCRT_804_19

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 > Abstract 

Aim: Self.expandable metallic stent (SEMS) placement has been considered as the preferred treatment to relieve jaundice in nonsurgical patients. However, 50% of stents become stenosed within 3.6 months due to tumor ingrowth and epithelial hyperplasia. This study aims to evaluate the feasibility and efficacy of a newly designed brachytherapy biliary drainage catheter (BBDC) loaded with 125I seeds for palliation of malignant biliary obstruction (MBO).
Methods: In this prospective study, patients with unresectable MBO underwent BBDC placement after SEMS placement at our center from September 2017 to April 2019.
Results: A total of 21 patients with MBO were enrolled. The technical and clinical success rates were 100%. Total bilirubin, direct bilirubin, alanine aminotransferase, alkaline phosphatase, cancer antigen 19.9, and carcinoembryonic antigen levels significantly decreased during the 1.month follow.up (P < 0.05). Four patients (19%) had minor complications. During the median follow.up of 299 days, 13 patients (61.9%) developed stent occlusion. The 6.month stent patency and survival rates were 73.5% and 79.2%, respectively. The median stent patency and survival were 279 and 454 days, respectively.
Conclusion: The use of BBDC loaded with 125I seeds is a feasible and effective method to prolong biliary stent patency in patients with MBO.

Keywords: 125I seed, biliary stent, brachytherapy, catheter drainage, clinical study, malignant biliary obstruction


How to cite this article:
Jiao D, Zhou X, Li Z, Bi Y, Zhang Q, Li J, Li L, Ren J, Han X. A newly designed biliary brachytherapy drainage catheter for patients with malignant biliary obstruction: A pilot study. J Can Res Ther 2020;16:286-91

How to cite this URL:
Jiao D, Zhou X, Li Z, Bi Y, Zhang Q, Li J, Li L, Ren J, Han X. A newly designed biliary brachytherapy drainage catheter for patients with malignant biliary obstruction: A pilot study. J Can Res Ther [serial online] 2020 [cited 2020 Jul 16];16:286-91. Available from: http://www.cancerjournal.net/text.asp?2020/16/2/286/285202




 > Introduction Top


Malignant biliary obstruction (MBO) can occur due to various causes, such as gallbladder cancer, cholangiocarcinoma, and pancreatic cancer, and detecting this at an unresectable stage signals poor prognosis.[1] Self-expandable metallic stent (SEMS) placement has been considered as the best approach to relieve jaundice in these patients.[2] However, 50% of stents become stenosed within 3–6 months due to tumor ingrowth and epithelial hyperplasia.[3] Hence, stents with longer patency are required to prolong the survival of patients with unresectable or metastatic MBO.

In 2012, Zhu et al.[4] reported that a radioactive biliary stent loaded with125 I seeds exhibited significantly prolonged stent patency when compared with conventional stents. However, the deployment process of the stent was complex, and the radioactive seeds could not be removed when complications occurred. In 2017, the investigators reported that SEMS combined with single125 I strands brachytherapy can be applied as a simple and effective treatment approach for MBO. However, a single125 I strand has a low cumulative brachytherapy dose. Furthermore, the fibrous connective tissue in the bile duct reduces the local irradiation effect.[5] In order to overcome these disadvantages, a brachytherapy biliary drainage catheter (BBDC) loaded with double125 I seed strands that simultaneously provide biliary drainage and intraluminal brachytherapy (ILBT) was designed. This catheter is easy to deploy and can be replenished with new125 I seeds to achieve a higher radiation dose. To the best of our knowledge, this is thefirst report that described the use of such a device for MBO.


 > Methods Top


Patients

This clinical research was approved by the Ethics Committee of theFirst Affiliated Hospital of Zhengzhou University. In the present prospective cohort study, patients within 18–80 years old, who had histologically confirmed MBO with unresectable or metastatic disease, or denied surgical treatment, and an Eastern Cooperative Oncology Group (ECOG) performance of 0–2, were enrolled. All patients underwent computed tomography (CT) or magnetic resonance cholangiopancreatography (MRCP) to evaluate the extent of the biliary obstruction before stenting. The exclusion criteria were as follows: (a) main portal vein tumor thrombus; (b) severe coagulation defect; (c) refractory ascites; (d) refusal to undergo the procedure; and (f) an ECOG performance of 3–4. Detail information is list in [Table 1].
Table 1: Patient characteristics

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Device

The newly designed biliary drainage catheter (Tuoren, Henan, China) used in the present study comprised three distinct ports [Figure 1]. The central port (internal diameter [ID] = 2.4 mm) provides external-internal bile drainage. This was lined with several lateral holes placed 15 cm away from the distal tip of the catheter. The other two ports (ID = 0.85 mm) were designed to carry radionuclides, located close to the central port, and 180° apart. The125 I radioactive seeds were inserted into both ports before deployment. The distal part of the radionuclide ports was closed at 5 cm from the tip to prevent the seeds from leaking into the duodenum. A radiopaque marker was placed at 1 cm from the last hole to facilitate the positioning of the catheter under fluoroscopy. For the precise placement and prevention of catheter slippage, a thread and a loop were employed (diameter = 2.0 cm).
Figure 1: Biliary brachytherapy drainage catheter loaded with125I seeds

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The125 I seeds (Said Biopharmaceutical Co., Ltd., Tianjin, China) were configured in a cylindrical brachytherapy source encapsulated by titanium. The size of each titanium capsule was 0.8 mm × 4.5 mm. The measured emissions were low-energy (35.5 keV γ) with a half-life of 59.6 days. The measured radioactivity of each seed was 0.72–0.81 mCi. The number of125 I seeds to be implanted was calculated using the following formula:

Number of125 I seeds required = (the biliary obstruction length [mm] +40/4.5) × 2

In order to prevent the seeds from withdrawing, a guidewire (0.018 inch in diameter, 20–30 length) was placed in both radionuclide ports. The ends of these ports were closed using medical adhesive tape.

Procedures

Before 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). First, under digital subtraction angiography 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. Next, a 0.035-inch guidewire was passed across the biliary obstruction into the duodenum, and this was exchanged with Amplatz Super Stiff Guidewires (Boston Scientific, Natick, MA, USA). Then, an 9 F × 23 cm sheath (Cordis, USA) was advanced along the stiff guidewire close to the site of the biliary stenosis or occlusion to establish a biopsy channel. Afterward, the tumor samples were obtained through a forceps biopsy device using a previously described technique of the investigators[5] [Figure 2]. Subsequently, a conventional 10.2 F external-internal biliary drainage catheter (Cook, USA) was placed across the stenosis. The patient was observed for the next few days for the resolution of the bile duct dilatation, improvement in the general condition of the patient, and the histopathology report of the biopsy samples.
Figure 2: (a) Percutaneous transhepatic cholangiography was performed to visualize the location and degree of biliary obstruction (arrow); (b) PTC biopsy was performed at the site of biliary obstruction using biopsy forceps through the 9F long sheath

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If the malignancy was confirmed by pathology, the patient underwent BBDC placement. The biliary stenosis was dilated using a 6-mm or 7-mm balloon catheter (Boston Scientific, USA). Then, a SEMS stent (diameter = 10 mm, length = 50 or 60 mm; Mich-tech, Nangjing, China) was deployed across the biliary stenosis or occlusion [Figure 3]. Finally, the stent deployment system was exchanged with the BBDC loaded with125 I seeds, and the device was fixed. Afterward, the position of the seeds was verified by single-photon emission computerized tomography (SPECT)/CT within 3 days [Figure 3]. The estimated radiation dose at reference point A (5 mm from the center) was calculated using a computerized treatment planning system (TPS).
Figure 3: (a and b) The preoperative magnetic resonance cholangiopancreatography and enhanced computed tomography revealed the stenosis of the common bile duct (white arrow) caused by the cholangiocarcinoma. (c) The brachytherapy biliary drainage catheter loaded with125I seeds was inserted across the SEMS stent up to the duodenum. (d) The single-photon emission computerized tomography/computed tomography revealed the precise intraluminal brachytherapy for biliary malignant stenosis without125I seed displacement or migration. (e and f) The cholangiogram and cross section of the computed tomography demonstrates the biliary patency at 1 month

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Cholangiography was performed to verify the position of the drainage catheter and patency of the stent at 1 month after the procedure. After the patency of the expanded stent was confirmed by cholangiography, the brachytherapy catheter was removed [Figure 3].

Definitions

The primary endpoints were technical success, clinical success, and median stent patency. The secondary endpoints were complications, patient survival, and pre- and post-operative changes in the biochemical indicators, hemogram, immune indicators, and tumor markers. Technical success was defined as the deployment of the BBDC with good contrast flow through the stent at 1 month. Clinical success was defined as a successful BBDC removal and a reduction in serum bilirubin by at least 75% of the pretreatment value within 1 month. Complications were classified according to the guidelines of the Society of Interventional Radiology Standards of Practice Committee.[6] Stent occlusion was defined as biliary dilatation on CT or magnetic resonance imaging (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 defined as the interval between stent placement and the development of stent occlusion. The procedure time was defined as the time required for the percutaneous transhepatic biopsy and implantation of the new BBDC.

Statistical analysis

Continuous variables were summarized as median or mean ± standard deviation. Paired-sample Student's t-test was used to compare the pre- and post-procedure indicators. Survival and stent patency time were calculated according to the Kaplan–Meier method, and a value of P < 0.05 was considered statistically significant. The calculations were performed using the SPSS software (version 17.0, SPSS, Chicago, Illinois, USA).


 > Results Top


The present study included 21 patients (11 males and 10 females), who had a mean age of 61.5 ± 11.3 years old (range: 39–78 years old). These patients underwent CT (n = 12), MRI (n = 4), or both (n = 5) for the evaluation of the site, extent, and cause of the biliary obstruction. Malignant pathologies were routinely diagnosed by forceps biopsy for all patients. The technical and clinical success rates were both 100%, with a mean procedure time of 59.4 min. The cholangiograms at 1 month following stent placement revealed adequate biliary drainage with decompression of the biliary ducts. The BBDC was removed from all patients after the confirmation of good stent patency. There was a significant improvement in serum bilirubin (SB), direct bilirubin (DB), alanine aminotransferase, and alkaline phosphatase after 1 month of the procedure [P < 0.01, [Table 2]. Meanwhile, the CA-199 and carcinoembryonic antigen (CEA) levels significantly decreased from 681.9 ± 740.8 (range: 125–3365 U/ml) and 7.85 ± 2.7 (range: 4.8–15.8 ng/ml) to 193.3 ± 152.7 (range: 55–675 U/ml) and 4.5 ± 1.4 (range: 2.6–7.2 ng/ml), respectively (P < 0.01). Furthermore, no125 I seeds were lost during the delivery or deployment, as confirmed by fluoroscopy and SPECT/CT. The mean activity of each seed was 0.77 mCi. The median estimated radiation dose at the reference point was 85.8 Gy, as calculated by TPS over 1 month.
Table 2: Pre- and post-treatment laboratory data

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Four patients (19%) had minor complications. Two patients experienced minor hemorrhage for 2 days, which spontaneously stopped. The other two patients had pancreatitis (serum amylase was not high, but the CT revealed a slight increase in fat density around the pancreas) and cholangitis (n = 1), and were treated with acid suppression, antibiotics, and nutritional support for 1 week.

During the mean follow-up period of 299 days (range: 95–501 days), 13 patients (61.9%) developed stent occlusion. Among these patients, nine patients (42.9%) underwent biliary re-intervention, whereas four patients (19.1%) had stent occlusion within the 6 months. The median stent patency was 279 days. The 3-, 6-, 9-, and 12-month stent patency rates were 95.2%, 73.5%, 61.7%, and 30.8%, respectively. During the follow-up period, 15 patients received chemotherapy (n = 13) and immunotherapy (n = 2). A total of seven patients died during the follow-up period, and the median overall survival was 454 days. The 3-, 6-, 9-, and 12-month survival rates were 95.2%, 79.2%, 61.7%, and 30.8%, respectively [Table 3].
Table 3: Procedural details, post-procedure outcomes and follow-up data

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 > Discussion Top


Surgical resection remains the only potentially curative treatment for MBO.[7] However, MBO patients with advanced-stage tumors are not suitable candidates for the surgery. Noncovered biliary stent placement is thefirst choice of palliative treatment for such cases. Unfortunately, this cannot prevent tumor ingrowth or overgrowth, leading to secondary stent occlusion. It has been reported that 50% of stent restenosis occurs within 3–6 months due to tumor ingrowth, overgrowth, or epithelial hyperplasia.[3] Hence, newer techniques are required to reduce the development of biliary restenosis. Many investigators have attempted various therapies to control the growth of biliary tumors, including intraductal radiofrequency ablation,[8],[9] photodynamic therapy,[10],[11] and intraluminal high-dose rate192 Ir radiation.[12] However, despite the use of these therapies, the median patency time ranges between 110 and 413 days.[8],[9],[10],[11],[12]

In recent years,125 I seeds have been used as the radioactive source for ILBT in the treatment of MBO. The duration of patency ranges from 129 to 381 days.[4],[13],[14],[15],[16],[17],[18],[19] To date, there are four methods for deploying125 I seeds. Liu et al.[13] reported the use of a plastic stent with lateral channels (0.7 mm) deployed across malignant stenosis by endoscopic retrograde cholangiopancreatography. However, the diameter of the drainage lumen was only 1.8 mm, thereby increasing the chances of stent blockage. Zhu et al.[4] described a two-step method by deploying an irradiation stent, followed by a conventional stent. However, the125 I seeds could not be removed or replaced, even if complications occurred. Chen et al.[15] reported the implantation of125 I seeds into a 3F catheter with both tips closed to form a single125 I strand. This strand was pressed outward by SEMS using a dual-guidewire technique, resulting in eccentric dose distribution. Finally, Jiao et al.[5] designed a small hole at 1–2 cm from the catheter, in which a single125 I strand could be placed at the center of the inner lumen of the stent. This single strand could be removed following brachytherapy. However, the tumor received a rapidly declining dose of the radionuclide. In order to overcome these technical limitations, a BBDC loaded with double125 I seed strands was designed. This design simultaneously achieves drainage and brachytherapy. Double125 I strands provide a better dose distribution than a single strand. In addition, the catheter can be removed or replaced when brachytherapy-related complications occur, or the ILBT terminates.

This preliminary study demonstrates the safety and feasibility of the novel drainage catheter plus double125 I seeds for the palliative treatment of MBO. The technical and clinical success rates (100%), and early complication rate (19.1%) was similar to that of previous studies,[4],[13],[14],[15],[16],[17],[18],[19] suggesting that the three-lumen catheter does not increase complications or decrease the clinical success. Furthermore, the double125 I seed strands with low-dose-rate ILBT provided a median stent patency time of 279 days, which is encouraging. Tumor control is an important goal in clinical practice. However, stent patency was chosen as the primary endpoint due to the following reasons:first, tumors become compressed by the implanted stent, which makes it difficult to accurately assess the tumor response; second, although all the patients had malignant obstructive jaundice, there were patients with pancreatic cancer, cholangiocarcinoma and gallbladder cancer, which made the tumor response evaluation difficult; third, stent patency is one of the important factors that affected the long-term survival of patients with malignant obstructive jaundice. The stent patency time was long in the present study, which reflects good local intraluminal tumor control.

In order to increase the success rate, many modifications were performed in the insertion technique. First, a 10.2 F (not an 8.5 F) external-internal drainage catheter was initially used for drainage, and to perform the forceps biopsy procedure, in order to reduce the resistance between the catheter and tissue, since the drainage catheter was not circular due to its three-port structure. Second, balloon dilatation was used before the BBDC placement, allowing the new irregularly-shaped drainage catheter to be replaced without disturbing the SEMS. Third, SPECT/CT was used to evaluate the distribution of the low-dose rate125 I energy, which provided greater visualization of the ILBT. Nevertheless, the relationship between the amount of radioactive concentration and dose calculated by the TPS remains unclear. Hence, further studies are needed to determine whether the radioactive dose received is adequate.

The median estimated radiation dose at dose reference point A was 85.5 Gy, as calculated by the TPS for the 1-month ILBT. This was larger than the median radiation dose of 52.3 Gy reported in the previous study of the investigators, in which a single125 I strand was used.[18] The present dose gives the better capacity to control the tumor ingrowth and overgrowth, and the possibility to result in longer stent patency. This may explain the low incidence of the 6-month stent occlusion (19.1%) in the present study. To date, no specialized TPS is available for125 I seed strands. Therefore, there is a need to determine the precise dose curves in future.

The present study has several limitations. First, the sample size was small, and there was no control group. These limitations may confound the results, especially the stent patency rate and survival time. Second, it was difficult to evaluate the tumor response following stent placement, which possibly influenced the objective evaluation of the tumor inhibition by ILBT. Third, a particular TPS for low-dose rate ILBT with125 I seeds has not yet been developed. This means that the optimum safety dosimetry is not yet accurate.


 > Conclusion Top


The newly designed BBDC loaded with125 I seeds represents a feasible palliative method for MBO. This simultaneously provides drainage and brachytherapy. In the future, this technique may provide a novel palliative treatment to prolong survival.

Acknowledgments

We would like to thank Medjaden Bioscience Limited for assisting in the preparation of this manuscript.

Financial support and sponsorship

This work was supported by the Science and technology project of Henan Province (2017-2019) (172102310388) and the Key Scientific Research Projects of Higher Education Institutions in Henan Province (20A320024) and Provincial and ministerial youth projects, Henan Medical Science and Technology Public Relations Program 2019 (SB201902015).

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

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Lee E, Gwon DI, Ko GY, Sung KB, Yoon HK, Shin JH, et al. Percutaneous biliary covered stent insertion in patients with malignant duodenobiliary obstruction. Acta Radiol 2015;56:166-73.  Back to cited text no. 1
    
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Xiao J, Zhu J, Liu Z, Wan R, Li Y, Xiao W. Role of surgical treatment for hepatolithiasis-associated intrahepatic cholangiocarcinoma: A retrospective study in a single institution. J Cancer Res Ther 2017;13:756-60.  Back to cited text no. 7
    
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Guan L, Wang J, Gao K, Zhai R. Percutaneous intraductal radiofrequency ablation combined with biliary stent placement for malignant biliary obstruction: A case report and review of the literature. J Cancer Res Ther 2016;12:C221-4.  Back to cited text no. 8
    
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Mukewar S, Gupta A, Baron TH, Gores G, Furutani K, Haddock MG, et al. Endoscopically inserted nasobiliary catheters for high dose-rate brachytherapy as part of neoadjuvant therapy for perihilar cholangiocarcinoma. Endoscopy 2015;47:878-83.  Back to cited text no. 12
    
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Liu Y, Lu Z, Zou DW, Jin ZD, Liu F, Li SD, et al. Intraluminal implantation of radioactive stents for treatment of primary carcinomas of the peripancreatic-head region: A pilot study. Gastrointest Endosc 2009;69:1067-73.  Back to cited text no. 13
    
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Guo Y, Chen J, Liu Y, Hu YH, Li ZS. Iodine-125 biliary stent for palliative treatment of locally advanced gallbladder cancer. Endoscopy 2010;42 Suppl 2:E259-60.  Back to cited text no. 14
    
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Chen Y, Wang XL, Yan ZP, Wang JH, Cheng JM, Gong GQ, et al. The use of (1)(2)(5)I seed strands for intraluminal brachytherapy of malignant obstructive jaundice. Cancer Biother Radiopharm 2012;27:317-23.  Back to cited text no. 15
    
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Hasimu A, Gu JP, Ji WZ, Zhang HX, Zhu DW, Ren WX. Comparative study of percutaneous transhepatic biliary stent placement with or without iodine-125 seeds for treating patients with malignant biliary obstruction. J Vasc Interv Radiol 2017;28:583-93.  Back to cited text no. 19
    


    Figures

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