Endobiliary radiofrequency ablation for malignant biliary obstruction

Istanbul, Turkey

Endobiliary radiofrequency ablation for malignant biliary obstruction

Halil Alis, Cetin Sengoz, Murat Gonenc, Mustafa Uygar Kalayci and Ali Kocatas

Istanbul, Turkey

BACKGROUND:The cornerstone of palliative treatment for inoperable extrahepatic cholangiocarcinoma is the relief of malignant biliary obstruction. The most commonly applied method is endoscopic stenting. However, the procedure can be complicated with stent obstruction. In this respect, endobiliary radiofrequency ablation may serve as an adjunctive tool for prolonging the stent patency.

METHODS:Patients who underwent endoscopic retrograde cholangiopancreatography for differential diagnosis and/ or palliative treatment after the diagnosis of inoperable extrahepatic cholangiocarcinoma between March 2011 and January 2012 were analyzed. Those in whom endobiliary radiofrequency ablation and endoscopic stenting was successfully performed were included in the study. Technical details of the procedure, duration of stent patency, length of hospital stay, short-term morbidity and mortality rate were documented.

RESULTS:Seventeen patients were analyzed, and 10 patients were included in the study. The morbidity and mortality rate within the first 30 days after the procedure was 20% and 0%, respectively. In 2 patients, mild pancreatitis occurred because of the endobiliary procedure. In 1 patient, endobiliary decompression could not be achieved, and therefore, percutaneous transhepatic biliary drainage was carried out. The median duration of stent patency in 9 patients with successful biliary decompression was 9 months (range 6-15).

CONCLUSION:Endobiliary radiofrequency ablation seems to be safe and feasible as a palliative measure and may prolong the stent patency and overall survival in patients with malignant biliary obstruction due to inoperable extrahepatic cholangiocarcinoma.

(Hepatobiliary Pancreat Dis Int 2013;12:423-427)

obstructive jaundice; cholangicarcinoma; Klatskin tumor; endobiliary stenting; radiofrequency ablation

Introduction

The vast majority of patients with extrahepatic cholangiocarcinoma present with malignant biliary obstruction, and most have advanced disease and thus can only be offered palliative treatment. The cornerstone of palliative treatment is the relief of malignant biliary obstruction, which can be achieved surgically, endoscopically, or radiologically.[2]

Endoscopic retrograde biliary drainage by endoscopic stenting, if possible, is a desirable method for palliation of malignant biliary obstruction.[3,4]However, the major drawback of endoscopic stenting is that the patency of endoscopic stent is limited to a median duration of 120 days with plastic stents and 130-217 days with selfexpandable metalic stents (SEMSs).[5-14]This is mainly due to tumor in- or over-growth, biofilm deposition, biliary sludge, or formation of granulation tissue, all of which may result in ongoing or recurrent biliary obstruction that causes significant morbidity and mortality.[6]

Several methods such as the use of organic polymers to coat SEMSs, substituting alloys like nitinol for stainless steel, or endobiliary photodynamic therapy, have been proposed for increasing the duration of stent patency in malignant biliary obstruction but have not been proven to be effective by sufficient data.[6]

Radiofrequency (RF) energy produces a high frequency electric current, which leads to coagulation necrosis in the tissue.[15,16]RF ablation (RFA) has been increasingly accepted in the last 15 years with promising results for various medical indications, and its use for cancer is approved by the US Food and Drug Administration. Recently, preliminary reports basedon the use of endobiliary RFA in malignant biliary obstruction have emerged.[6,17]Two major advantages of RFA in this setting are brought forward. First, it reduces the tumor load, and thus, delays tumor growth, both of which may potentially prolong stent patency.[6,17]And second, endobiliary RFA may eventually constitute a form of neoadjuvant therapy in unresectable cholangiocarcinoma.[6]

In this study, the patients with unresectable extrahepatic cholangiocarcinoma were treated by endoscopic stenting after the application of endobiliary RFA, and the management and the outcome of the patients were described.

Methods

The study was a retrospective analysis. The patients with unresectable extrahepatic cholangiocarcinoma who had undergone endoscopic retrograde cholangiopancreatography (ERCP) for differential diagnosis and/or palliative treatment between March 2011 and January 2012 were recruited, and those who had successfully undergone endobiliary RFA and endoscopic stenting were also included. All of the patients were fully informed about details and complications of the procedure, and were requested to sign an informed consent form.

All patients underwent a detailed clinical and radiological investigation for differential diagnosis. The medical data of all patients were evaluated by a multidisciplinary team including surgeons, radiologists, medical and radiation oncologists, and pathologists. Patients who refused to join the study or to sign the informed consent form, patients with Bismuth type II, III or IV hilar cholangiocarcinoma, patients in whom endoscopic procedure could not be completed, and patients with benign biliary stricture were excluded from the study.

ERCP was performed under standard operating conditions with a Fujinon EVE 200 duodenoscope (Fujinon, Tokyo, Japan). Prophylactic antibiotherapy with ceftriaxone (1 g, intravenous) (Rocephin?, Roche, Istanbul, Turkey) was done prior to the procedure. Conscious anesthesia was induced with intravenous propofol (2 mg/kg) and fentanyl (2 mg/kg). The patient was placed in a left lateral decubitus position. After the cannulation of the common bile duct, a cholangiogram was obtained to assess the length, diameter, and location of the biliary stricture. Habib EndoHPB (Emcision?, London, UK) was used for RFA. An RF catheter was placed through the biliary stricture under fluoroscopic guidance (Fig.). The catheter had a bipolar RF probe, which was 8F (2.6 mm), 1.8 m long, compatible with standard (3.2-mm working channel) side-viewing endoscopes, and could be passed over 0.035-inch guidewires. The catheter has two ring electrodes 8 mm apart with the distal electrode 5 mm from the leading edge, providing local coagulative necrosis over a 2.5-cm length. An RF generator (1500 RF generator; RITA Medical Systems Inc., California, USA) producing electrical energy at 400 kHz at 10 W was utilized. Total duration of an RFA session was two minutes with two 40-second periods and a final 10-second period of RFA seperated with 15-second breaks. At the end of RFA session, a control cholangiogram was obtained to rule out skipped areas of biliary stricture, which would necessitate an additional RFA session, after a 60-second rest period without removing the catheter (Fig.). Thereafter, the RF catheter was withdrawn without removing the guidewire. A 10F silicone-covered SEMS (Niti-S TM Biliary Stent, Taewoong Medical Co., Ltd., Gyeonggi-Do, Korea) was introduced over the previously placed guidewire. Endoscopic stent wasplaced according to the findings of index cholangiogram. After the placement of the stent, a cholangiogram was obtained to confirm the correct position of endoscopic stent and whether the patency of entire biliary tree could be achieved (Fig.).

Physical examination, measurement of complete blood count, and measurement of serum amylase levels were carried out in all patients. Those who had no positive clinical signs or biochemical results were discharged at the end of 48 hours after the procedure. The patients who were suspected to have any complications were promptly evaluated and treated in the in-hospital setting.

The patients were referred to medical oncologist for adjuvant chemotherapy. All patients, except one who was found to be a poor candidate for systemic chemotherapy, had a combined chemotherapy with gemcitabine and cisplatin.

All of the patients were followed regularly after the procedure, and no patients were lost to follow-up. Demographics, inoperability criteria, the location of malignant stricture, details of previous interventions, technical details of the procedure, the duration of stent patency, length of hospital stay, short-term morbidity and mortality rate were documented.

Results

Seventeen patients with inoperable extrahepatic cholangiocarcinoma were recruited for the study. ERCP or endobiliary RFA was not attempted or not successful in 7 patients. Therefore, 10 patients who had successful ERCP with endobiliary RFA and endoscopic stenting were included in the study.

Inoperability criteria in 17 patients were as follows: unresectability (9 patients); extremely high-risk for surgery due to preexisting comorbidities (6); and refusal to undergo surgery (2). Three of 7 patients in whom ERCP or endobiliary RFA was not attempted or not successful were found to have Bismuth type II or III hilar cholangiocarcinoma, both of which were not suitable for placement of RFA probe. The other two patients developed severe respiratory distress due to significant comorbidities during the procedure. In the last 2 patients, the common bile duct could not be cannulated due to severe fibrosis of major duodenal papilla, which was found to be benign after histopathological examination of endoscopic biopsy materials.

The mean age and female-to-male ratio was 62.3± 8.7 years (48-74) and 3/7, respectively. The indications for palliative treatment were unresectable tumor dueto locally advanced disease (6 patients), metastatic disease (2), and considerably high-risk for surgery due to comorbidities (2). Bismuth type I hilar and distal cholangiocarcinoma was present in 4 and 6 patients, respectively. None of the patients had undergone any surgical or endoscopic intervention before the procedure.

Table.Technical details, and the results of outcome variables

The procedure was uneventful in all patients. In spite of a successful session of endobiliary RFA and endoscopic stent application, biliary decompression could not be achieved in one patient at the end of 10 days after the endoscopic procedure. Therefore, the patient was referred to the interventional radiologist for the application of percutaneous transhepatic biliary drainage. Two patients developed abdominal pain and 8 to 10-fold elevation in serum amylase levels within the first 12 hours after the procedure, and thus, were considered to have post-ERCP pancreatitis. Post-ERCP pancreatitis in both patients had a mild course, and had subsided with conservative treatment without any complications.

The median duration of stent patency in 9 patients with successful biliary decompression was 9 months (range 6-15). Of these 9 patients, 1 patient died in the 8th month after the endoscopic procedure because of preexisting comorbidities. The details of the procedure and the results of the study are illustrated in Table.

Discussion

Steel and his coworkers[6]recently published a clinical study including 22 patients with malignant biliary obstruction who were palliated by endobiliary RFA and stenting. They reported that the technique was safe and effective for the palliation of such patients. In this series, we observed the safety and the feasibility of this procedure in a similar group of patients as it could be carried out with minor complications and no mortality. The median duration of stent patency in the present study is within the normal ranges given for endoscopicSEMS application alone. However, 9 of the 10 patients in this study have not experienced any episode of obstructive jaundice within the follow-up period. Therefore, we can only speculate that endobiliary RFA is at least as effective as endoscopic stenting alone.

The main concern about endobiliary RFA is the likelihood of an iatrogenic thermal injury to adjacent structures, which might lead to perforation in involved or intact bile ducts or vessel injury.[6]This may occur because of inappropriate placement of an RF catheter or a stricture shorter than 2.5 cm, which is the exact distance between two RF electrodes. The use of a bipolar system instead of a single electrode, which delivers a greater energy radially from a focus, significantly decreases the risk of thermal injury. In the bipolar system, energy travels between the 2 electrodes, and thus, the heat spreads to a larger field.[1]Furthermore, if the RF catheter is in a correct position, the bulk of tumor avoids the radial spread of heat energy. One can never be sure about whether the RF catheter is placed in an optimal position by a cholangiogram under fluoroscopic guidance. The only way to place the RF catheter in an optimal position, as well as to explore the bile ducts for possible thermal injury, is performing the procedure under direct vision using a babyscope. Nevertheless, if an inadvertent bile duct injury occurs, it can still be managed by combined endoscopic and percutaneous approach in most cases.

Fortunately, we did not experience any iatrogenic bile duct injuries of clinical significance in this series. Because covered SEMSs may lead to inadvertent obstruction of intrahepatic side branches when applied for hilar strictures, they are generally not prefered for palliation of hilar cholangiocarcinomas.[5]The only reason of our preference for covered SEMS was the fear of an iatrogenic thermal injury to involved or intact bile ducts, which may eventually result in biliary sepsis. Moreover, we already excluded the patients with Bismuth type II, III and IV hilar cholangiocarcinoma. In those who had Bismuth type I hilar cholangiocarcinoma, we did not find any problem, which was confirmed by final cholangiogram showing the patency of both hepatic ducts. This may be partially due to remodeling effect of RFA therapy on tumoral mass.

我們看到大多數(shù)家庭經(jīng)過一場場疾病走向陽光和健康，但也有的父母像軒軒的爸爸媽媽那樣，在疾病面前自己先變成了弱者，總在心里向疾病求饒，替寶寶“負罪”，失去了一顆平常健康的心態(tài)，給寶寶的性格打上一些特殊的烙?。杭膊∈且粋€砝碼，可以換來我想得到的一切，尤其是有需要就能滿足的優(yōu)越感。因此，我們常聽見有的父母說：“寶寶剛剛大病一場，現(xiàn)在變得特別嬌氣，有點要求不滿足，就哭得像個淚人兒似的?！庇械母改竸t說：“生完病，寶寶的脾氣特別大，不像以前那樣乖，總想迫使大人讓著他?！?/p>

The use of endobiliary RFA, which is expected to increase the duration of stent patency, along with covered SEMS seems paradoxal at first sight because biliary covered SEMSs are much more durable when compared to plastic stents and uncovered SEMSs and usually keep their patencies as long as the expected survival of such patients. If the median diameter of biliary strictures in this study (range 1.5-2.0 mm) was considered, however, we could not apply a SEMS in any size without reducing the bulk of tumor mass in most of the cases. In this respect, endobiliary RFA served as an adjunctive tool for the application of large caliber SEMSs, which not only facilitates biliary flow but also improves patency rates.[5]

In other words, we performed endobiliary RFA to reduce the size of tumor mass, and thus, to enable the placement of a SEMS, preferentially a large caliber one, through a biliary stricture that did not allow the placement of a SEMS of any size initially. And we used covered SEMSs because of the fear of an inadvertent bile duct injury. Moreover, endobiliary RFA therapy can be repeated in patients who admit for recurrent biliary obstruction due to tumor in- or over-growth.

From an optimistic perspective, single or multiple sessions of endobiliary RFA can result in an increase in overall survival in patients with locally advanced disease. In this series, 2 patients with locally advanced disease did well without any recurrent episodes for 13 and 15 months, respectively, which are beyond the median survival estimated for such patients.

The present study has important weakness with its retrospective nature. Second, the presence of a control group composed of either endoscopic stenting alone or photodynamic therapy plus endoscopic stenting would be of a great value. Third, long-term outcomes, which would show the actual impact of RFA on both stent patency and overall survival, are lacking. Therefore, it is yet impossible to claim that endobiliary RFA is superior to other methods. However, the study has already been designed as a pilot study aiming to investigate the safety and the feasibility of endobiliary RFA.

In conclusion, endobiliary RFA therapy is feasible and safe for palliative treatment of malignant biliary obstruction due to distal and Bismuth type I hilar extrahepatic cholangiocarcinoma, and may have a positive impact on stent patency and overall survival. However, large-volume randomized controlled clinical trials are necessary to assess its exact place in palliative treatment of extrahepatic cholangiocarcinomas.

Contributors:AH and SC proposed the study. AH, SC, KMU, and KA performed research and wrote the first draft. GM collected and analyzed the data. All authors contributed to the design and interpretation of the study and to further drafts. AH is the guarantor.

Funding:None.

Ethical approval:The study was approved by the institutional review board of the hospital.

Competing interest:No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.

1 Wade TP, Prasad CN, Virgo KS, Johnson FE. Experience with distal bile duct cancers in U.S. Veterans Affairs hospitals: 1987-1991. J Surg Oncol 1997;64:242-245.

2 Fong Y, Blumgart LH, Lin E, Fortner JG, Brennan MF. Outcome of treatment for distal bile duct cancer. Br J Surg 1996;83:1712-1715.

3 Andersen JR, S?rensen SM, Kruse A, Rokkjaer M, Matzen P. Randomised trial of endoscopic endoprosthesis versus operative bypass in malignant obstructive jaundice. Gut 1989;30:1132-1135.

4 Shepherd HA, Royle G, Ross AP, Diba A, Arthur M, Colin-Jones D. Endoscopic biliary endoprosthesis in the palliation of malignant obstruction of the distal common bile duct: a randomized trial. Br J Surg 1988;75:1166-1168.

5 Kim JH. Endoscopic stent placement in the palliation of malignant biliary obstruction. Clin Endosc 2011;44:76-86.

6 Steel AW, Postgate AJ, Khorsandi S, Nicholls J, Jiao L, Vlavianos P, et al. Endoscopically applied radiofrequency ablation appears to be safe in the treatment of malignant biliary obstruction. Gastrointest Endosc 2011;73:149-153.

7 Cheng JL, Bruno MJ, Bergman JJ, Rauws EA, Tytgat GN, Huibregtse K. Endoscopic palliation of patients with biliary obstruction caused by nonresectable hilar cholangiocarcinoma: efficacy of self-expandable metallic Wallstents. Gastrointest Endosc 2002;56:33-39.

8 Dumas R, Demuth N, Buckley M, Peten EP, Manos T, Demarquay JF, et al. Endoscopic bilateral metal stent placement for malignant hilar stenoses: identification of optimal technique. Gastrointest Endosc 2000;51:334-338.

9 Chennat J, Waxman I. Initial performance profile of a new 6F self-expanding metal stent for palliation of malignant hilar biliary obstruction. Gastrointest Endosc 2010;72:632-636.

10 Park do H, Lee SS, Moon JH, Choi HJ, Cha SW, Kim JH, et al. Newly designed stent for endoscopic bilateral stent-in-stent placement of metallic stents in patients with malignant hilar biliary strictures: multicenter prospective feasibility study (with videos). Gastrointest Endosc 2009;69:1357-1360.

11 Lee JH, Kang DH, Kim JY, Lee SM, Kim do H, Park CW, et al. Endoscopic bilateral metal stent placement for advanced hilar cholangiocarcinoma: a pilot study of a newly designed Y stent. Gastrointest Endosc 2007;66:364-369.

12 Kim JY, Kang DH, Kim HW, Choi CW, Kim ID, Hwang JH, et al. Usefulness of slimmer and open-cell-design stents for endoscopic bilateral stenting and endoscopic revision in patients with hilar cholangiocarcinoma (with video). Gastrointest Endosc 2009;70:1109-1115.

13 Chahal P, Baron TH. Expandable metal stents for endoscopic bilateral stent-within-stent placement for malignant hilar biliary obstruction. Gastrointest Endosc 2010;71:195-199.

14 Kawamoto H, Tsutsumi K, Fujii M, Harada R, Kato H, Hirao K, et al. Endoscopic 3-branched partial stent-in-stent deployment of metallic stents in high-grade malignant hilar biliary stricture (with videos). Gastrointest Endosc 2007;66: 1030-1037.

15 Cho YK, Kim JK, Kim MY, Rhim H, Han JK. Systematic review of randomized trials for hepatocellular carcinoma treated with percutaneous ablation therapies. Hepatology 2009;49:453-459.

16 Mulier S, Ruers T, Jamart J, Michel L, Marchal G, Ni Y. Radiofrequency ablation versus resection for resectable colorectal liver metastases: time for a randomized trial? An update. Dig Surg 2008;25:445-460.

17 Monga A, Gupta R, Ramchandani M, Rao GV, Santosh D, Reddy DN. Endoscopic radiofrequency ablation of cholangiocarcinoma: new palliative treatment modality (with videos). Gastrointest Endosc 2011;74:935-937.

July 24, 2012

Accepted after revision October 30, 2012

Author Affiliations: General Surgery Clinics, Dr. Sadi Konuk Training and Research Hospital, Istanbul 34147, Turkey (Alis H, Gonenc M, Kalayci MU and Kocatas A); General Surgery Clinics, Mugla Public Hospital, Mugla 48162, Turkey (Sengoz C)

Halil Alis, MD, General Surgery Clinics, Dr. Sadi Konuk Training and Research Hospital, Istanbul 34147, Turkey (Tel: 90-212-4147171; Fax: 90-212-5424491; Email: halilalis@gmail.com)

? 2013, Hepatobiliary Pancreat Dis Int. All rights reserved.

10.1016/S1499-3872(13)60066-1