CLINICAL STUDY
Percutaneous Transhepatic Cholangiography and Intraductal Radiofrequency Ablation Combined with Biliary Stent Placement for Malignant Biliary Obstruction Teng-Fei Li, MD, Guo-Hao Huang, MMM, Zhen Li, MD, Chang-Fu Hao, MD, Jian-Zhuang Ren, Xu-Hua Duan, MD, Kai Zhang, MMM, Chen Chen, MD, Xin-Wei Han, MD, De-Chao Jiao, MD, Meng-Fan Zhang, MD, and Yan-Li Wang, MD
ABSTRACT Purpose: To determine the safety and feasibility of percutaneous transhepatic cholangiography (PTC) and intraductal radiofrequency (RF) ablation combined with biliary stent placement for malignant biliary obstruction. Materials and Methods: Data from patients with unresectable malignant biliary obstruction who underwent PTC, intraductal RF ablation, and biliary stent placement (n ¼ 12) or PTC and biliary stent placement only (control group; n ¼ 14) were reviewed. Postoperative complications, jaundice remission, and stent patency were assessed. Results: All procedures were successful. No severe complications (eg, biliary bleeding, perforation) occurred. Two experimental group patients developed cholangitis, which resolved with conservative treatment. The 1-week jaundice remission and 3-month stent patency rates were similar in both groups, but the 6-month stent patency rate was higher in the experimental group (P o .05). In the experimental group, one death occurred as a result of gastrointestinal hemorrhage (unrelated to stent placement) by 3 months, and there were two cases of recurrent jaundice by 6 months. The latter two patients underwent repeat PTC, ablation, and stent placement. In the control group, one death occurred as a result of hepatic failure caused by progressive jaundice at 3 months, and another death resulted from disseminated intravascular coagulation caused by jaundice recurrence at 138 days after stent placement. In addition, seven patients developed jaundice recurrence (50–151 d after stent placement). PTC and repeat stent placement were performed in these patients. Conclusions: Percutaneous transhepatic cholangiography and intraductal RF ablation combined with biliary stent placement for malignant biliary obstruction is safe and feasible and effectively prolongs stent patency time.
ABBREVIATIONS PTC = percutaneous transhepatic cholangiography, RF = radiofrequency
From the Department of Interventional Radiology (T.-F.L., G.-H.H., Z.L., J.-Z.R., X.-H.D., K.Z., C.C., X.-W.H., D.-C.J., M.-F.Z., Y.-L.W.), The First Affiliated Hospital of Zhengzhou University; and Interventional Institute (T.-F.L., G.-H.H., Z.L., J.-Z.R., X.-H.D., K.Z., C.C., X.-W.H., D.-C.J., M.-F.Z., Y.-L.W.) and College of Public Health (C.-F.H.), Zhengzhou University, Zhengzhou, People’s Republic of China. Received October 17, 2014; final revision received and accepted January 30, 2015. Address correspondence to X.-W.H., Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P. R. China; E-mail: [email protected] None of the authors have identified a conflict of interest. & SIR, 2015 J Vasc Interv Radiol 2015; 26:715–721 http://dx.doi.org/10.1016/j.jvir.2015.01.037
Bile duct drainage techniques, especially metal stent insertion, can effectively ameliorate jaundice and preserve function in patients with inoperable malignant biliary obstruction However, stent implantation is merely a palliative treatment, and further tumor growth can cause stent obstruction. In patients with malignant biliary obstruction, the median patency time of a metallic biliary stent can be 6–9 months (1). At present, stent obstruction can be treated with only balloon dilation and stent replacement. The discovery of a new palliative treatment that directly destroys tumor cells and can be combined with existing palliative interven-
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tions might be useful for delaying tumor progression, prolonging stent patency, improving quality of life, and possibly conserving medical resources. Recently, intraductal radiofrequency (RF) ablation was used to treat malignant tumors involving the bile duct; however, most such ablation treatments were conducted endoscopically, and the number of cases was limited (2). There have been few reports (3,4) about intraductal RF ablation conducted with the use of percutaneous transhepatic cholangiography (PTC). In the present retrospective study, we compared intraductal RF ablation conducted via PTC followed by a biliary stent with simple stent insertion. We aimed to determine the safety, feasibility, and short-term efficacy of PTC and intraductal RF ablation combined with biliary stent placement in patients with malignant biliary obstruction.
MATERIALS AND METHODS Subject Selection This study was approved by the ethics committee of the First Affiliated Hospital of Zhengzhou University. From April 2013 to August 2014, we retrospectively reviewed the clinical and imaging data of 69 patients with obstructive jaundice, including 27 patients who had undergone intraductal RF ablation combined with biliary stent placement and 42 patients who had undergone stent insertion only. Among these patients, 43 had also received other antineoplastic therapies such as surgery, systemic chemotherapy, and radioactive particle implantation and were therefore excluded from the study. By August 2014, 26 patients had been enrolled into the study. Of these, 12 patients (seven men and five women) had undergone intraductal RF ablation combined with biliary stent placement and were included in the experimental group. The other 14 patients (eight men and six women) had undergone stent insertion only and were included in the control group. The patients’ demographic characteristics are shown in Table 1.
Equipment RF Ablation Catheter. We used the Habib EndoHPB (EMcision, London, United Kingdom), which has been certified by the U.S. Food and Drug Administration and the European Union. This bipolar RF probe, which has a diameter of 8 F (2.6 mm) and a length of 1.8 m, can be introduced by using a 0.035-inch guide wire. At the distal end of the catheter, there are two ring electrodes spaced 8 mm apart. The most distal electrode is 5 mm from the end of the catheter. This catheter can be used to create a 2.5-mm-wide focus of coagulation necrosis. RF Generator. We used a RITA 1500X system (RITA Medical Systems, Fremont, California), which has a frequency of 400 kHz and an output power of 10
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Table 1 . Patient Demographic Data and Characteristics Experimental Characteristic Sex Male Female
Group (n ¼ 12)
Control Group (n ¼ 14)
7
8
5
6
53
60
Hilar
2
3
cholangiocarcinoma Cancer of middle/lower
7
8
Pancreatic cancer Carcinoma of ampulla
2 1
1 1
Gallbladder carcinoma
0
1
Location of obstruction Hilar and left/right bile
2
2
0
1
4 6
3 8
10 2
7 7
Median age (y) Tumor type
thirds of bile duct
duct Ductuli hepaticus communis and upper CBD Middle CBD Lower CBD and ampulla Method of diagnosis Bile duct biopsy Imaging data CBD ¼ common bile duct.
W. The ablation time was 1–2 minutes, and the location of the catheter was changed after a 1-minute pause.
Treatment Intraductal RF ablation combined with biliary stent placement was performed by two physicians, one with 8 years of experience and the other with 20 years of experience. Patients were placed in a supine position on a digital subtraction angiography table, and general anesthesia was induced in all patients. Then, standardized PTC was carried out under fluoroscopic guidance. PTC was used to visualize the location, extent, and degree of bile duct obstruction. A hydrophilic guide wire (Cook, Bloomington, Indiana) was introduced through the obstructed lesion into the duodenum. In the experimental group patients, a bipolar RF ablation catheter was inserted, and the electrode was placed at the site of tumor obstruction under fluoroscopic guidance, such that the target tissue was between the electrodes. If the lesion was longer than 2.5 cm, it was ablated section by section, and the procedure was started at the distal end of the obstruction. If the tumor involved the left and right intrahepatic bile ducts, ablation was conducted on both sides. The output power used was 10 W, and the ablation time was 1.5–2 minutes. After RF ablation, an uncovered self-expanding nitinol stent (Micro-Tech, Nanjing, China) with a diameter of 10 mm was inserted. The stent extended
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at least 1 cm beyond either end of the occluded section. Cholangiography was used to check that the bile duct was clear (Fig 1). Patients in the control group underwent only stent insertion, and the stent type and technique were the same as those in the experimental group. After stent insertion in the experimental group patients, the procedure path was sealed with an embolization coil in two patients and with gelatin sponge in 10 patients. In the control group, the path was sealed with an embolization coil in three patients and with gelatin sponge in 11 patients.
Efficacy Evaluation and Follow-up Patients were administered prophylactic antibiotics and symptomatic treatments after the procedure. At 1 week
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after the procedure, the patients were examined for remission of jaundice and short-term complications, and the serum bilirubin concentration was recorded. After discharge, stent patency and patient survival were recorded by follow-up outpatient visits or telephone interviews. Stent patency was demonstrated if jaundice was not observed, direct bilirubin level was normal, and bile duct expansion was not displayed on magnetic resonance (MR) imaging or ultrasonography during postoperative follow-up. If jaundice was observed and liver function tests showed an increase in the total or direct bilirubin levels, or if jaundice was not observed but the total or direct bilirubin levels were found to have increased during follow-up, contrast-enhanced computed tomography (CT) or MR imaging examination was
Figure 1. Images from a 62-year-old man with a highly differentiated adenocarcinoma of the distal third of the bile duct confirmed by rapid pathologic diagnostic forceps biopsy (a). The arrow indicates the obstruction. (b) An RF ablation catheter is inserted into the obstruction. The arrow indicates the distal end of the ablation catheter. (c) Cholangiography after ablation shows that the obstruction has been relieved. (d) A self-expanding metallic stent is inserted after the ablation.
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performed to confirm stent obstruction. On the imaging examination, the bile duct above the stent appeared obviously expanded if stent blockage had occurred, indicating the loss of patency. We repeated RF ablation and inserted a new stent in two patients in the experimental group (Fig 2) and inserted a new stent in five patients in the control group. If the new stent could not be fully expanded, it was dilated with a balloon. All patients were followed-up once per month for 6 months after the procedure.
Statistical Analysis Statistical analysis was performed by using SPSS software (version 19.0; IBM, Armonk, New York).
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Biochemical indices are presented as mean ⫾ standard deviation. Numeric data were analyzed by using the χ2 test or Fisher exact probability test. Measurement data were analyzed by t test. The significance level was α ¼ 0.05.
RESULTS Procedure The procedures were successfully performed in all patients. In the experimental group, 14 self-expanding metallic stents were inserted, including four stents implanted in two patients with hilar (ie, Bismuth IV) cholangiocarcinoma (each patient had two stents
Figure 2. Images from a 59-year-old man with distal common bile duct carcinoma who developed jaundice recurrence 5.2 months after stent placement. (a) PTC confirmed stent occlusion (arrow). (b) A guide wire is inserted through the obstructed stent. An ablation catheter is introduced, and the obstruction is ablated. The arrow indicates the end of the ablation catheter. (c) After the ablation, a new stent is inserted. The white arrow indicates the previously placed stent, and the black arrow indicates the new stent. (d) Cholangiography after stent placement shows that the obstruction has been relieved.
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inserted). In these patients, a percutaneous transhepatic approach was used to puncture the left and right intrahepatic bile ducts, and ablation was separately conducted at both sites. Then, two stents were inserted to form a “Y” shape. In the control group, 16 selfexpanding metallic stents were inserted, including two stents in each of two patients with hilar cholangiocarcinoma.
Complications and Management In both groups, there was no electrocardiographic abnormality observed during surgery. No instances of bile duct perforation, peribiliary sepsis, or hemorrhage occurred. Postoperatively, three patients in the experimental group presented with symptoms of cholangitis (1, 3, and 8 h after the procedure), such as abdominal pain, chills, and fever, which were resolved with antibiotic therapy and other conservative treatments. Repeat liver function and routine blood tests after these treatments showed that the laboratory values had returned to baseline levels. There were no cases of hemobilia, perforation, bile leak, or pancreatitis.
Outcomes and Follow-up In both groups, jaundice was relieved by 1 week postoperatively, and abdominal distension and loss of appetite were almost completely resolved. The postoperative decrease in the total and direct bilirubin levels did not significantly differ between the two groups (Table 2). All patients were fully followed up via outpatient visits or telephone interviews. Three months after the intervention, one patient in the experimental group died of gastrointestinal bleeding that was unrelated to biliary stent placement, and this case was excluded from further analysis. The other patients in the experimental group (n ¼ 11) were alive and had no recurrence of jaundice. In the control group (n ¼ 14), one patient died of hepatic failure as a result of progressive jaundice. In addition, two patients in the control group had recurrence of jaundice at 50 and 57
days after the intervention. Contrast-enhanced CT or MR imaging showed that the bile duct above the stent was obviously expanded. On the basis of this finding and the increase in bilirubin levels, we suspected stent obstruction, which was confirmed by repeat PTC. A balloon catheter (Bard Peripheral Vascular, Tempe, Arizona) was introduced to dilate the lumen, and then a new stent was inserted. At 6 months postoperatively, no further deaths had occurred in the experimental group, but two patients had developed recurrent jaundice. Both patients underwent repeat PTC to confirm stent occlusion and received new stents after RF ablation of the obstructed stent was performed. In the control group, one more death occurred at 138 days after stent placement; this patient died of disseminated intravascular coagulation as a result of the recurrence of jaundice. In addition, there were five new cases of recurrent jaundice (72–151 d after the intervention) in the control group. Repeat PTC in these patients confirmed stent occlusion, and a new stent was inserted. Stent patency at 3 months did not significantly differ between the two groups (experimental group, 11 of 11; control group, 11 of 14; P ¼ .23), but stent patency at 6 months was higher in the experimental group than in the control group (experimental group, nine of 11; control group, five of 14; P ¼ .042).
DISCUSSION Self-expanding metal stent insertion has become the standard treatment for patients with unresectable malignant biliary obstruction who are expected to live longer than 3 months (5,6). However, tumor growth through the stent mesh, epithelial cell hyperplasia, and biliary sludge, among other complications, lead to a 50% stent restenosis rate within 6 months after intervention (1). The occlusion rate is even higher in patients with hilar cholangiocarcinoma (7). The failure of uncovered metallic stents can potentially be corrected with the insertion of self-expanding metallic stents covered with a polytetrafluoroethylene membrane (8–11). However,
Table 2 . Decrease in Total Bilirubin Levels and Direct Bilirubin Levels in the Two Study Groups Measurement
Experimental Group (n ¼ 12)
Control Group (n ¼ 14)
Total bilirubin level (μmol/L) Before intervention
287.2 ⫾ 123.5
254.2 ⫾ 108.5
After intervention
154.3 ⫾ 76.1
139.1 ⫾ 87.0
Difference P value
123.9 ⫾ 68.1
115.2 ⫾ 56.8 .476
Direct bilirubin level (μmol/L) Before intervention After intervention
183.4 ⫾ 73.9 105.1 ⫾ 57.9
Difference
78.3 ⫾ 39.4
P value
148.4 ⫾ 58.0 90.8 ⫾ 59.3 57.6 ⫾ 29.7 .140
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whether the use of covered stents increases the risk of cholecystitis remains controversial. Several studies suggest the superiority of covered self-expanding metallic stents (12,13). However, some studies have shown that the incidence of cholecystitis and pancreatitis is increased after the insertion of covered stents (1,14–20). RF ablation is a new, effective, minimally invasive technology that is increasingly being used in the treatment of solid tumors, especially small hepatocellular carcinomas and metastatic hepatic carcinomas. However, the technique has only recently been used in the treatment of malignant bile duct obstruction, and related reports are rare. The introduction of the bipolar RF catheter has opened up the possibility of a new type of treatment for bile duct carcinoma. In 2008, Khorsandi et al (3) conducted intraductal RF ablation of the bile duct in pigs, and found that an output power of 5–10 W and an ablation time of 2 minutes were safe and effective; the authors recommended these parameters for clinical use. Steel et al (2) performed endoscopic intraductal RF ablation in 22 patients with malignant obstructive jaundice and reported that the short- and long-term stent occlusion rates were low, and that no serious complications occurred. Therefore, the authors concluded that this technique was safe and feasible for clinical use (2). As the technique of endoscopic intraductal RF ablation became more widely used, Mizandari et al (4), in 2013, performed intraductal RF ablation via PTC under fluoroscopic guidance in 39 patients with malignant obstructive jaundice. All procedures were successfully completed, and no severe procedure-related complications occurred. In addition, only one case of recurrent stent obstruction (42 d after the procedure) was found during follow-up. These results demonstrated the feasibility, safety, and effectiveness of the PTC ablation technique. Further experiments in a swine model showed that the potential complications of this technique were burn injury of the local tissue and difficulty in stent insertion after ablation (3). In addition, there is a risk of bleeding and abscess formation during the ablation process (21,22). In the present study, there were no complications such as biliary tract bleeding, perforation, and bile leakage among the 12 patients in the experimental group. In addition, stents were successfully inserted into the bile duct after ablation. These results show that the parameters used in the present study are safe. Three patients in the experimental group developed abdominal pain, chills, and fever after the procedure. Two of these patients had Bismuth IV hilar cholangiocarcinoma and required RF ablation of the left and right intrahepatic bile ducts. The third patient had long segmental occlusion of the common bile duct and underwent RF ablation section by section. In these patients, the total ablation time was too long and the ablation range was too large. We speculate that the necrotic tumor tissue could have therefore become
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dislodged, and this could have caused poor bile drainage and bile duct inflammation. In view of this, administration of prophylactic antibiotic agents as single doses may be necessary. The rates of jaundice remission at 1 week and stent patency at 3 months after the procedure did not significantly differ between the experimental and control groups. We consider that, in a short period, the tumor would not grow fast enough to block the stent. At 6 months after the procedure, the stent patency rate was much higher in the experimental group than in the control group; this indicates that tumor growth had indeed been inhibited and stent patency had been prolonged in the experimental group. Monga et al (23) reported the case of a patient with middle common bile duct carcinoma treated with intraductal RF ablation. Choledochoscopy performed 2 weeks after the procedure showed that, compared with the findings before RF ablation, the tumor tissue appeared pale and destroyed; the tumor blood vessels had disappeared and the lumen had enlarged, which indicated that RF ablation can destroy tumor tissue to some extent. However, this research was elementary and short-term. PTC and intraductal RF ablation combined with biliary stent placement are associated with a low retrograde infection rate. For high-level obstructions in particular, PTC and ablation are much simpler than endoscopic treatment. However, in the case of lesions located in the hilar region and common bile duct, ablation treatment should be performed cautiously because excessive charring may occur, causing perforation. At present, ablation cannot ensure effective tissue necrosis at depth; therefore, ablation can safely treat only a part of a deep tumor. The present study has some limitations. Long-term follow-up is required to determine whether intraductal RF ablation can prolong survival in patients with malignant biliary obstruction. We emphasize that RF ablation is a palliative local thermal damage treatment, and it cannot achieve radical tumor elimination. The heat penetration depth in this technique is limited. Therefore, the coagulation zone is too small in patients who have tumors that involve the bile duct but do not originate from the bile duct epithelium, such as gallbladder carcinoma, liver cancer, or pancreatic cancer. Hence, the indications of intraductal RF ablation remain to be discussed. In addition, the treatment procedure should also be further researched. We need to determine whether a single treatment is sufficient or whether repeated cyclical treatments increase tumor destruction and improve patient survival. If the latter is true, we need to determine the optimal treatment cycle. Therefore, many questions need to be researched further. In conclusion, PTC intraductal RF ablation combined with biliary stent placement for malignant biliary obstruction is feasible and safe. This preliminary clinical
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investigation revealed that the treatment is safe and has good short-term efficacy. However, the long-term effects and optimal treatment plan remain to be determined.
ACKNOWLEDGMENT We thank all the patients and their families who participated in this study.
REFERENCES 1. Loew BJ, Howell DA, Sanders MK, et al. Comparative performance of uncoated, self-expanding metal biliary stents of different designs in 2 diameters: Final results of an international multicenter, randomized, controlled trial. Gastrointest Endosc 2009; 70(3):445–453. 2. Steel AW, Postgate AJ, Khorsandi S, et al. Endoscopically applied radiofrequency ablation appears to be safe in the treatment of malignant biliary obstruction. Gastrointest Endosc 2011; 73(1):149–153. 3. Khorsandi SE, Zacharoulis D, Vavra P, et al. The modern use of radiofrequency energy in surgery, endoscopy and interventional radiology. European Surgery 2008; 40(5):204–210. 4. Mizandari M, Pai M, Xi F, et al. Percutaneous intraductal radiofrequency ablation is a safe treatment for malignant biliary obstruction: feasibility and early results. Cardiovasc Intervent Radiol 2013; 36(3):814–819. 5. Shepherd HA, Royle G, Ross AP, et al. Endoscopic biliary endoprosthesis in the palliation of malignant obstruction of the distal common bile duct: a randomized trial. Br J Surg 1988; 75(12):1166–1168. 6. Andersen JR, Sorensen SM, Kruse A, et al. Randomised trial of endoscopic endoprosthesis versus operative bypass in malignant obstructive jaundice. Gut 1989; 30(8):1132–1135. 7. Dahlstrand U, Sandblom G, Eriksson LG, et al. Primary patency of percutaneously inserted self-expanding metallic stents in patients with malignant biliary obstruction. HPB (Oxford) 2009; 11(4):358–363. 8. O’Brien S, Hatfield AR, Craig PI, et al. A three year follow up of self expanding metal stents in the endoscopic palliation of longterm survivors with malignant biliary obstruction. Gut 1995; 36(4):618–621. 9. Zoepf T, Jakobs R, Arnold JC, et al. Palliation of nonresectable bile duct cancer: improved survival after photodynamic therapy. Am J Gastroenterol 2005; 100(11):2426–2430.
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10. Shim CS, Lee YH, Cho YD, et al. Preliminary results of a new covered biliary metal stent for malignant biliary obstruction. Endoscopy 1998; 30 (4):345–350. 11. Ballinger AB, McHugh M, Catnach SM, et al. Symptom relief and quality of life after stenting for malignant bile duct obstruction. Gut 1994; 35(4):467–470. 12. Gwon DL, Ko GY, Yoon HK, et al. Safety and efficacy of percutaneous Y-configured covered stent placement for malignant hilar biliary obstruction: a prospective, pilot study. J Vasc Interv Radiol 2012; 23(4): 528–534. 13. Lee SJ, Kim MD, Lee MS, et al. Comparison of the efficacy of covered versus uncovered metallic stents in treating inoperable malignant common bile duct obstruction: a randomized trial. J Vasc Interv Radiol 2014; 25(12):1912–1920. 14. Yoon WJ, Lee JK, Lee KH, et al. A comparison of covered and uncovered Wallstents for the management of distal malignant biliary obstruction. Gastrointest Endosc 2006; 63(7):996–1000. 15. Isayama H, Komatsu Y, Tsujino T, et al. A prospective randomised study of “covered” versus “uncovered” diamond stents for the management of distal malignant biliary obstruction. Gut 2004; 53(5):729–734. 16. Kahaleh M, Tokar J, Conaway MR, et al. Efficacy and complications of covered Wallstents in malignant distal biliary obstruction. Gastrointest Endosc 2005; 61(4):528–533. 17. Hatzidakis A, Krokidis M, Kalbakis K, et al. ePTFE/FEP-covered metallic stents for palliation of malignant biliary disease: can tumor ingrowth be prevented? Cardiovasc Intervent Radiol 2007; 30(5):950–958. 18. Shah RJ, Howell DA, Desilets DJ, et al. Multicenter randomized trial of the spiral Z-stent compared with the Wallstent for malignant biliary obstruction. Gastrointest Endosc 2003; 57(7):830–836. 19. Suk KT, Kim HS, Kim JW, et al. Risk factors for cholecystitis after metal stent placement in malignant biliary obstruction. Gastrointest Endosc 2006; 64(4):522–529. 20. Ortner ME, Caca K, Berr F, et al. Successful photodynamic therapy for nonresectable cholangiocarcinoma: a randomized prospective study. Gastroenterology 2003; 125(5):1355–1363. 21. Sutherland LM, Williams JA, Padbury RT, et al. Radiofrequency ablation of liver tumors: a systematic review. Arch Surg 2006; 141(2):181–190. 22. Mulier S, Ruers T, Jamart J, et al. Radiofrequency ablation versus resection for resectable colorectal liver metastases: time for a randomized trial? An update. Dig Surg 2008; 25(6):445–460. 23. Monga A, Gupta R, Ramchandani M, et al. Endoscopic radiofrequency ablation of cholangiocarcinoma: new palliative treatment modality (with videos). Gastrointest Endosc 2011; 74(4):935–937.
Percutaneous Transhepatic Cholangiography and Intraductal Radiofrequency Ablation Combined with Biliary Stent Placement for Malignant Biliary Obstruction Teng-Fei Li, MD, Guo-Hao Huang, MMM, Zhen Li, MD, Chang-Fu Hao, MD, Jian-Zhuang Ren, Xu-Hua Duan, MD, Kai Zhang, MMM, Chen Chen, MD, Xin-Wei Han, MD, De-Chao Jiao, MD, Meng-Fan Zhang, MD, and Yan-Li Wang, MD
ABSTRACT Purpose: To determine the safety and feasibility of percutaneous transhepatic cholangiography (PTC) and intraductal radiofrequency (RF) ablation combined with biliary stent placement for malignant biliary obstruction. Materials and Methods: Data from patients with unresectable malignant biliary obstruction who underwent PTC, intraductal RF ablation, and biliary stent placement (n ¼ 12) or PTC and biliary stent placement only (control group; n ¼ 14) were reviewed. Postoperative complications, jaundice remission, and stent patency were assessed. Results: All procedures were successful. No severe complications (eg, biliary bleeding, perforation) occurred. Two experimental group patients developed cholangitis, which resolved with conservative treatment. The 1-week jaundice remission and 3-month stent patency rates were similar in both groups, but the 6-month stent patency rate was higher in the experimental group (P o .05). In the experimental group, one death occurred as a result of gastrointestinal hemorrhage (unrelated to stent placement) by 3 months, and there were two cases of recurrent jaundice by 6 months. The latter two patients underwent repeat PTC, ablation, and stent placement. In the control group, one death occurred as a result of hepatic failure caused by progressive jaundice at 3 months, and another death resulted from disseminated intravascular coagulation caused by jaundice recurrence at 138 days after stent placement. In addition, seven patients developed jaundice recurrence (50–151 d after stent placement). PTC and repeat stent placement were performed in these patients. Conclusions: Percutaneous transhepatic cholangiography and intraductal RF ablation combined with biliary stent placement for malignant biliary obstruction is safe and feasible and effectively prolongs stent patency time.
ABBREVIATIONS PTC = percutaneous transhepatic cholangiography, RF = radiofrequency
From the Department of Interventional Radiology (T.-F.L., G.-H.H., Z.L., J.-Z.R., X.-H.D., K.Z., C.C., X.-W.H., D.-C.J., M.-F.Z., Y.-L.W.), The First Affiliated Hospital of Zhengzhou University; and Interventional Institute (T.-F.L., G.-H.H., Z.L., J.-Z.R., X.-H.D., K.Z., C.C., X.-W.H., D.-C.J., M.-F.Z., Y.-L.W.) and College of Public Health (C.-F.H.), Zhengzhou University, Zhengzhou, People’s Republic of China. Received October 17, 2014; final revision received and accepted January 30, 2015. Address correspondence to X.-W.H., Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P. R. China; E-mail: [email protected] None of the authors have identified a conflict of interest. & SIR, 2015 J Vasc Interv Radiol 2015; 26:715–721 http://dx.doi.org/10.1016/j.jvir.2015.01.037
Bile duct drainage techniques, especially metal stent insertion, can effectively ameliorate jaundice and preserve function in patients with inoperable malignant biliary obstruction However, stent implantation is merely a palliative treatment, and further tumor growth can cause stent obstruction. In patients with malignant biliary obstruction, the median patency time of a metallic biliary stent can be 6–9 months (1). At present, stent obstruction can be treated with only balloon dilation and stent replacement. The discovery of a new palliative treatment that directly destroys tumor cells and can be combined with existing palliative interven-
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tions might be useful for delaying tumor progression, prolonging stent patency, improving quality of life, and possibly conserving medical resources. Recently, intraductal radiofrequency (RF) ablation was used to treat malignant tumors involving the bile duct; however, most such ablation treatments were conducted endoscopically, and the number of cases was limited (2). There have been few reports (3,4) about intraductal RF ablation conducted with the use of percutaneous transhepatic cholangiography (PTC). In the present retrospective study, we compared intraductal RF ablation conducted via PTC followed by a biliary stent with simple stent insertion. We aimed to determine the safety, feasibility, and short-term efficacy of PTC and intraductal RF ablation combined with biliary stent placement in patients with malignant biliary obstruction.
MATERIALS AND METHODS Subject Selection This study was approved by the ethics committee of the First Affiliated Hospital of Zhengzhou University. From April 2013 to August 2014, we retrospectively reviewed the clinical and imaging data of 69 patients with obstructive jaundice, including 27 patients who had undergone intraductal RF ablation combined with biliary stent placement and 42 patients who had undergone stent insertion only. Among these patients, 43 had also received other antineoplastic therapies such as surgery, systemic chemotherapy, and radioactive particle implantation and were therefore excluded from the study. By August 2014, 26 patients had been enrolled into the study. Of these, 12 patients (seven men and five women) had undergone intraductal RF ablation combined with biliary stent placement and were included in the experimental group. The other 14 patients (eight men and six women) had undergone stent insertion only and were included in the control group. The patients’ demographic characteristics are shown in Table 1.
Equipment RF Ablation Catheter. We used the Habib EndoHPB (EMcision, London, United Kingdom), which has been certified by the U.S. Food and Drug Administration and the European Union. This bipolar RF probe, which has a diameter of 8 F (2.6 mm) and a length of 1.8 m, can be introduced by using a 0.035-inch guide wire. At the distal end of the catheter, there are two ring electrodes spaced 8 mm apart. The most distal electrode is 5 mm from the end of the catheter. This catheter can be used to create a 2.5-mm-wide focus of coagulation necrosis. RF Generator. We used a RITA 1500X system (RITA Medical Systems, Fremont, California), which has a frequency of 400 kHz and an output power of 10
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Table 1 . Patient Demographic Data and Characteristics Experimental Characteristic Sex Male Female
Group (n ¼ 12)
Control Group (n ¼ 14)
7
8
5
6
53
60
Hilar
2
3
cholangiocarcinoma Cancer of middle/lower
7
8
Pancreatic cancer Carcinoma of ampulla
2 1
1 1
Gallbladder carcinoma
0
1
Location of obstruction Hilar and left/right bile
2
2
0
1
4 6
3 8
10 2
7 7
Median age (y) Tumor type
thirds of bile duct
duct Ductuli hepaticus communis and upper CBD Middle CBD Lower CBD and ampulla Method of diagnosis Bile duct biopsy Imaging data CBD ¼ common bile duct.
W. The ablation time was 1–2 minutes, and the location of the catheter was changed after a 1-minute pause.
Treatment Intraductal RF ablation combined with biliary stent placement was performed by two physicians, one with 8 years of experience and the other with 20 years of experience. Patients were placed in a supine position on a digital subtraction angiography table, and general anesthesia was induced in all patients. Then, standardized PTC was carried out under fluoroscopic guidance. PTC was used to visualize the location, extent, and degree of bile duct obstruction. A hydrophilic guide wire (Cook, Bloomington, Indiana) was introduced through the obstructed lesion into the duodenum. In the experimental group patients, a bipolar RF ablation catheter was inserted, and the electrode was placed at the site of tumor obstruction under fluoroscopic guidance, such that the target tissue was between the electrodes. If the lesion was longer than 2.5 cm, it was ablated section by section, and the procedure was started at the distal end of the obstruction. If the tumor involved the left and right intrahepatic bile ducts, ablation was conducted on both sides. The output power used was 10 W, and the ablation time was 1.5–2 minutes. After RF ablation, an uncovered self-expanding nitinol stent (Micro-Tech, Nanjing, China) with a diameter of 10 mm was inserted. The stent extended
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at least 1 cm beyond either end of the occluded section. Cholangiography was used to check that the bile duct was clear (Fig 1). Patients in the control group underwent only stent insertion, and the stent type and technique were the same as those in the experimental group. After stent insertion in the experimental group patients, the procedure path was sealed with an embolization coil in two patients and with gelatin sponge in 10 patients. In the control group, the path was sealed with an embolization coil in three patients and with gelatin sponge in 11 patients.
Efficacy Evaluation and Follow-up Patients were administered prophylactic antibiotics and symptomatic treatments after the procedure. At 1 week
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after the procedure, the patients were examined for remission of jaundice and short-term complications, and the serum bilirubin concentration was recorded. After discharge, stent patency and patient survival were recorded by follow-up outpatient visits or telephone interviews. Stent patency was demonstrated if jaundice was not observed, direct bilirubin level was normal, and bile duct expansion was not displayed on magnetic resonance (MR) imaging or ultrasonography during postoperative follow-up. If jaundice was observed and liver function tests showed an increase in the total or direct bilirubin levels, or if jaundice was not observed but the total or direct bilirubin levels were found to have increased during follow-up, contrast-enhanced computed tomography (CT) or MR imaging examination was
Figure 1. Images from a 62-year-old man with a highly differentiated adenocarcinoma of the distal third of the bile duct confirmed by rapid pathologic diagnostic forceps biopsy (a). The arrow indicates the obstruction. (b) An RF ablation catheter is inserted into the obstruction. The arrow indicates the distal end of the ablation catheter. (c) Cholangiography after ablation shows that the obstruction has been relieved. (d) A self-expanding metallic stent is inserted after the ablation.
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performed to confirm stent obstruction. On the imaging examination, the bile duct above the stent appeared obviously expanded if stent blockage had occurred, indicating the loss of patency. We repeated RF ablation and inserted a new stent in two patients in the experimental group (Fig 2) and inserted a new stent in five patients in the control group. If the new stent could not be fully expanded, it was dilated with a balloon. All patients were followed-up once per month for 6 months after the procedure.
Statistical Analysis Statistical analysis was performed by using SPSS software (version 19.0; IBM, Armonk, New York).
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Biochemical indices are presented as mean ⫾ standard deviation. Numeric data were analyzed by using the χ2 test or Fisher exact probability test. Measurement data were analyzed by t test. The significance level was α ¼ 0.05.
RESULTS Procedure The procedures were successfully performed in all patients. In the experimental group, 14 self-expanding metallic stents were inserted, including four stents implanted in two patients with hilar (ie, Bismuth IV) cholangiocarcinoma (each patient had two stents
Figure 2. Images from a 59-year-old man with distal common bile duct carcinoma who developed jaundice recurrence 5.2 months after stent placement. (a) PTC confirmed stent occlusion (arrow). (b) A guide wire is inserted through the obstructed stent. An ablation catheter is introduced, and the obstruction is ablated. The arrow indicates the end of the ablation catheter. (c) After the ablation, a new stent is inserted. The white arrow indicates the previously placed stent, and the black arrow indicates the new stent. (d) Cholangiography after stent placement shows that the obstruction has been relieved.
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inserted). In these patients, a percutaneous transhepatic approach was used to puncture the left and right intrahepatic bile ducts, and ablation was separately conducted at both sites. Then, two stents were inserted to form a “Y” shape. In the control group, 16 selfexpanding metallic stents were inserted, including two stents in each of two patients with hilar cholangiocarcinoma.
Complications and Management In both groups, there was no electrocardiographic abnormality observed during surgery. No instances of bile duct perforation, peribiliary sepsis, or hemorrhage occurred. Postoperatively, three patients in the experimental group presented with symptoms of cholangitis (1, 3, and 8 h after the procedure), such as abdominal pain, chills, and fever, which were resolved with antibiotic therapy and other conservative treatments. Repeat liver function and routine blood tests after these treatments showed that the laboratory values had returned to baseline levels. There were no cases of hemobilia, perforation, bile leak, or pancreatitis.
Outcomes and Follow-up In both groups, jaundice was relieved by 1 week postoperatively, and abdominal distension and loss of appetite were almost completely resolved. The postoperative decrease in the total and direct bilirubin levels did not significantly differ between the two groups (Table 2). All patients were fully followed up via outpatient visits or telephone interviews. Three months after the intervention, one patient in the experimental group died of gastrointestinal bleeding that was unrelated to biliary stent placement, and this case was excluded from further analysis. The other patients in the experimental group (n ¼ 11) were alive and had no recurrence of jaundice. In the control group (n ¼ 14), one patient died of hepatic failure as a result of progressive jaundice. In addition, two patients in the control group had recurrence of jaundice at 50 and 57
days after the intervention. Contrast-enhanced CT or MR imaging showed that the bile duct above the stent was obviously expanded. On the basis of this finding and the increase in bilirubin levels, we suspected stent obstruction, which was confirmed by repeat PTC. A balloon catheter (Bard Peripheral Vascular, Tempe, Arizona) was introduced to dilate the lumen, and then a new stent was inserted. At 6 months postoperatively, no further deaths had occurred in the experimental group, but two patients had developed recurrent jaundice. Both patients underwent repeat PTC to confirm stent occlusion and received new stents after RF ablation of the obstructed stent was performed. In the control group, one more death occurred at 138 days after stent placement; this patient died of disseminated intravascular coagulation as a result of the recurrence of jaundice. In addition, there were five new cases of recurrent jaundice (72–151 d after the intervention) in the control group. Repeat PTC in these patients confirmed stent occlusion, and a new stent was inserted. Stent patency at 3 months did not significantly differ between the two groups (experimental group, 11 of 11; control group, 11 of 14; P ¼ .23), but stent patency at 6 months was higher in the experimental group than in the control group (experimental group, nine of 11; control group, five of 14; P ¼ .042).
DISCUSSION Self-expanding metal stent insertion has become the standard treatment for patients with unresectable malignant biliary obstruction who are expected to live longer than 3 months (5,6). However, tumor growth through the stent mesh, epithelial cell hyperplasia, and biliary sludge, among other complications, lead to a 50% stent restenosis rate within 6 months after intervention (1). The occlusion rate is even higher in patients with hilar cholangiocarcinoma (7). The failure of uncovered metallic stents can potentially be corrected with the insertion of self-expanding metallic stents covered with a polytetrafluoroethylene membrane (8–11). However,
Table 2 . Decrease in Total Bilirubin Levels and Direct Bilirubin Levels in the Two Study Groups Measurement
Experimental Group (n ¼ 12)
Control Group (n ¼ 14)
Total bilirubin level (μmol/L) Before intervention
287.2 ⫾ 123.5
254.2 ⫾ 108.5
After intervention
154.3 ⫾ 76.1
139.1 ⫾ 87.0
Difference P value
123.9 ⫾ 68.1
115.2 ⫾ 56.8 .476
Direct bilirubin level (μmol/L) Before intervention After intervention
183.4 ⫾ 73.9 105.1 ⫾ 57.9
Difference
78.3 ⫾ 39.4
P value
148.4 ⫾ 58.0 90.8 ⫾ 59.3 57.6 ⫾ 29.7 .140
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whether the use of covered stents increases the risk of cholecystitis remains controversial. Several studies suggest the superiority of covered self-expanding metallic stents (12,13). However, some studies have shown that the incidence of cholecystitis and pancreatitis is increased after the insertion of covered stents (1,14–20). RF ablation is a new, effective, minimally invasive technology that is increasingly being used in the treatment of solid tumors, especially small hepatocellular carcinomas and metastatic hepatic carcinomas. However, the technique has only recently been used in the treatment of malignant bile duct obstruction, and related reports are rare. The introduction of the bipolar RF catheter has opened up the possibility of a new type of treatment for bile duct carcinoma. In 2008, Khorsandi et al (3) conducted intraductal RF ablation of the bile duct in pigs, and found that an output power of 5–10 W and an ablation time of 2 minutes were safe and effective; the authors recommended these parameters for clinical use. Steel et al (2) performed endoscopic intraductal RF ablation in 22 patients with malignant obstructive jaundice and reported that the short- and long-term stent occlusion rates were low, and that no serious complications occurred. Therefore, the authors concluded that this technique was safe and feasible for clinical use (2). As the technique of endoscopic intraductal RF ablation became more widely used, Mizandari et al (4), in 2013, performed intraductal RF ablation via PTC under fluoroscopic guidance in 39 patients with malignant obstructive jaundice. All procedures were successfully completed, and no severe procedure-related complications occurred. In addition, only one case of recurrent stent obstruction (42 d after the procedure) was found during follow-up. These results demonstrated the feasibility, safety, and effectiveness of the PTC ablation technique. Further experiments in a swine model showed that the potential complications of this technique were burn injury of the local tissue and difficulty in stent insertion after ablation (3). In addition, there is a risk of bleeding and abscess formation during the ablation process (21,22). In the present study, there were no complications such as biliary tract bleeding, perforation, and bile leakage among the 12 patients in the experimental group. In addition, stents were successfully inserted into the bile duct after ablation. These results show that the parameters used in the present study are safe. Three patients in the experimental group developed abdominal pain, chills, and fever after the procedure. Two of these patients had Bismuth IV hilar cholangiocarcinoma and required RF ablation of the left and right intrahepatic bile ducts. The third patient had long segmental occlusion of the common bile duct and underwent RF ablation section by section. In these patients, the total ablation time was too long and the ablation range was too large. We speculate that the necrotic tumor tissue could have therefore become
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dislodged, and this could have caused poor bile drainage and bile duct inflammation. In view of this, administration of prophylactic antibiotic agents as single doses may be necessary. The rates of jaundice remission at 1 week and stent patency at 3 months after the procedure did not significantly differ between the experimental and control groups. We consider that, in a short period, the tumor would not grow fast enough to block the stent. At 6 months after the procedure, the stent patency rate was much higher in the experimental group than in the control group; this indicates that tumor growth had indeed been inhibited and stent patency had been prolonged in the experimental group. Monga et al (23) reported the case of a patient with middle common bile duct carcinoma treated with intraductal RF ablation. Choledochoscopy performed 2 weeks after the procedure showed that, compared with the findings before RF ablation, the tumor tissue appeared pale and destroyed; the tumor blood vessels had disappeared and the lumen had enlarged, which indicated that RF ablation can destroy tumor tissue to some extent. However, this research was elementary and short-term. PTC and intraductal RF ablation combined with biliary stent placement are associated with a low retrograde infection rate. For high-level obstructions in particular, PTC and ablation are much simpler than endoscopic treatment. However, in the case of lesions located in the hilar region and common bile duct, ablation treatment should be performed cautiously because excessive charring may occur, causing perforation. At present, ablation cannot ensure effective tissue necrosis at depth; therefore, ablation can safely treat only a part of a deep tumor. The present study has some limitations. Long-term follow-up is required to determine whether intraductal RF ablation can prolong survival in patients with malignant biliary obstruction. We emphasize that RF ablation is a palliative local thermal damage treatment, and it cannot achieve radical tumor elimination. The heat penetration depth in this technique is limited. Therefore, the coagulation zone is too small in patients who have tumors that involve the bile duct but do not originate from the bile duct epithelium, such as gallbladder carcinoma, liver cancer, or pancreatic cancer. Hence, the indications of intraductal RF ablation remain to be discussed. In addition, the treatment procedure should also be further researched. We need to determine whether a single treatment is sufficient or whether repeated cyclical treatments increase tumor destruction and improve patient survival. If the latter is true, we need to determine the optimal treatment cycle. Therefore, many questions need to be researched further. In conclusion, PTC intraductal RF ablation combined with biliary stent placement for malignant biliary obstruction is feasible and safe. This preliminary clinical
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investigation revealed that the treatment is safe and has good short-term efficacy. However, the long-term effects and optimal treatment plan remain to be determined.
ACKNOWLEDGMENT We thank all the patients and their families who participated in this study.
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