Endoscopy 2018; 50(08): 751-760
DOI: 10.1055/s-0043-124870
Original article
© Georg Thieme Verlag KG Stuttgart · New York

Efficacy and safety of endoscopic radiofrequency ablation for unresectable extrahepatic cholangiocarcinoma: a randomized trial

Jianfeng Yang*
Department of Gastroenterology, Hangzhou First People’s Hospital, Nanjing Medical University, Hangzhou, China
,
Jing Wang*
Hangzhou Geriatric Hospital, Hangzhou First People’s Hospital Group, Hangzhou, China
,
Haibin Zhou
Hangzhou Geriatric Hospital, Hangzhou First People’s Hospital Group, Hangzhou, China
,
Yifeng Zhou
Department of Gastroenterology, Hangzhou First People’s Hospital, Nanjing Medical University, Hangzhou, China
,
Yang Wang
Department of Gastroenterology, Hangzhou First People’s Hospital, Nanjing Medical University, Hangzhou, China
,
Hangbin Jin
Department of Gastroenterology, Hangzhou First People’s Hospital, Nanjing Medical University, Hangzhou, China
,
Qifeng Lou
Department of Gastroenterology, Hangzhou First People’s Hospital, Nanjing Medical University, Hangzhou, China
,
Xiaofeng Zhang
Department of Gastroenterology, Hangzhou First People’s Hospital, Nanjing Medical University, Hangzhou, China
› Author Affiliations
TRIAL REGISTRATION: Single-center, randomized, prospective trial NCT02592538 at clinicaltrials.gov
Further Information

Corresponding author

Xiaofeng Zhang, MD
Department of Gastroenterology
Hangzhou First People’s Hospital
Nanjing Medical University
#261 Huansha Road
Hangzhou, 310006
Zhejiang Province
China   
Fax: +86-0571-56006872   

Publication History

submitted 14 August 2017

accepted after revision 26 November 2017

Publication Date:
17 January 2018 (eFirst)

 

Abstract

Background Endoscopic placement of biliary stents to relieve jaundice is the main palliative treatment for unresectable extrahepatic cholangiocarcinoma. Endoscopic biliary radiofrequency ablation (RFA) has been reported to prolong stent patency, which may be beneficial in improving patient survival. However, available evidence is still insufficient, as most reported studies are retrospective case series. The aim of this study was to explore the clinical effect and safety of RFA in patients with unresectable extrahepatic cholangiocarcinoma.

Methods 65 patients with unresectable extrahepatic cholangiocarcinoma, except Bismuth type III and IV hilar cholangiocarcinoma, were enrolled and randomly underwent either RFA combined with biliary stenting (RFA + stent group; n = 32) or biliary stent only (stent-only group; n = 33). Overall survival time, stent patency period, and postoperative adverse events were recorded.

Results In the 21-month follow-up period, the overall mean survival time was significantly longer in the RFA + stent group than in the stent-only group (13.2 ± 0.6 vs. 8.3 ± 0.5 months; P < 0.001). The mean stent patency period of the RFA + stent group was also significantly longer than that of the stent-only group (6.8 vs. 3.4 months; P = 0.02). There was no significant difference in the incidence of postoperative adverse events between the two groups (6.3 % [2/32] vs. 9.1 % [3/33]; P = 0.67).

Conclusion Endoscopic RFA combined with stenting can significantly prolong survival and the stent patency period without increasing the incidence of adverse events in patients with extrahepatic cholangiocarcinoma patient, except Bismuth type III and IV hilar cholangiocarcinoma. This approach can be considered as a safe and effective palliative treatment for these patients.


#

Introduction

Extrahepatic cholangiocarcinoma is a malignant tumor with an increasing incidence, accounting for approximately 3 % of all malignant tumors of the digestive tract [1] [2]. Extrahepatic cholangiocarcinoma is divided into perihilar and distal extrahepatic cholangiocarcinoma at the level of the cystic duct [3]. The only opportunity for long-term survival of patients with extrahepatic cholangiocarcinoma remains surgical resection with negative pathological margins [4]. However, because of its special anatomical location and occult onset, early diagnosis of extrahepatic cholangiocarcinoma is difficult, and thus, surgical resectability is only 20 % – 30 % [5] [6]. For patients with unresectable extrahepatic cholangiocarcinoma, endoscopic placement of biliary stents to reduce or relieve jaundice is the main palliative treatment but does not extend patient survival [7], as the average survival time of these patients is only 6 – 8 months from diagnosis [8] [9]. Compared with distant cholangiocarcinoma, patients with Bismuth type III and IV hilar cholangiocarcinoma benefit less from endoscopic stent placement and have a worse prognosis [10]. As the tumor continues to grow, re-obstruction of the biliary stent can cause recurrent jaundice or recurrent cholangitis, as well as liver, retroperitoneal, and other systemic distant metastases [11]. Therefore, active control of tumor growth is key to prolonging patient survival and stent patency.

RFA is an effective local ablative therapy that has been used extensively in many solid organ malignancies, especially in hepatocellular carcinoma [12]. The working principle of RFA is the emission of heat energy via a bipolar probe by using high-frequency alternating current, which in turn causes localized tissue necrosis [13]. Percutaneous RFA treatment can lead to radical cure in stage A – C liver cancer for tumors < 3 cm in diameter [14]. A meta-analysis also showed that RFA can significantly improve survival time in patients with unresectable intrahepatic cholangiocarcinoma [15].

RFA has also been recently applied to treat unresectable malignant extrahepatic biliary obstruction. In 2011, Steel et al. [16] first reported on 22 cases of advanced biliary obstruction (16 cases of pancreatic cancer and 6 cases of cholangiocarcinoma) treated with endoscopic bile duct RFA using the Habib EndoHPB bipolar radiofrequency electrode (EMcision, London, UK). In all, 21 cases were successful, yielding a technical success rate of 95.5 %. Because of its simplicity and safety, the clinical applications of endoscopic RFA in the treatment of malignant biliary obstruction have expanded. Preliminary results show that RFA can significantly prolong stent patency, which may also be beneficial for improving patient survival [17] [18] [19]. However, the vast majority of studies reported to date have been retrospective case series of patients with malignant biliary obstruction treated with RFA, and very few have studied extrahepatic cholangiocarcinoma only. Therefore, whether RFA prolongs survival time and stent patency in patients with extrahepatic cholangiocarcinoma remains unknown, and further research is needed in this area.

We conducted a prospectively randomized and controlled study to investigate the effect of endoscopic RFA using a Habib EndoHPB bipolar radiofrequency electrode, combined with stent implantation on survival and stent patency. We also evaluated the incidence of adverse events in patients with extrahepatic cholangiocarcinoma.


#

Methods

Patients

Patients with extrahepatic cholangiocarcinoma diagnosed at Hangzhou First People’s Hospital were consecutively enrolled from October 2015 to May 2016. The diagnostic criteria were based on the National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology: Hepatobiliary Cancers-Evidence Blocks [20].

Inclusion criteria were: 1) age 18 – 75 years, male or female; 2) histologically or cytologically diagnosed cholangiocarcinoma; 3) local infiltration of large vessels or distant metastasis in the tumor confirmed by computed tomography, magnetic resonance cholangiopancreatography, or endoscopic ultrasound (EUS) and surgical unresectability; 4) initial treatment; 5) Karnofsky performance scores (KPS) of 50 points or higher; and (6) written informed consent signed by the patient.

Exclusion criteria were: 1) Bismuth type III and type IV hilar cholangiocarcinoma; 2) combined with other malignancies; 3) severe liver dysfunction (prothrombin time activity percentage ≤ 40 %) or kidney dysfunction (creatinine clearance rate < 10 mL/min or serum creatinine > 442 μmol/L); 4) women who were pregnant or lactating; 5) other treatments that may affect the clinical follow-up, such as radioactive particles, particle stent implantation, or chemotherapy; and 6) alcohol and/or substance abuse or poor compliance as determined by the physician (including psychiatric disorders).


#

Study design

The study used a prospectively randomized and controlled design. Patients with extrahepatic cholangiocarcinoma were randomly assigned to two groups in a 1:1 ratio: an RFA + stent group and a stent-only group. The RFA + stent group underwent RFA combined with biliary stenting; the stent-only group simply underwent biliary stent placement. The order was generated by a random number table. Investigators performing follow-up were unaware of clinical data and treatment grouping until the end of the study.

Antibiotics, quinolone or cephalosporin, were administered 1 hour before RFA in all patients. Patients with long strictures (> 3 cm) in the RFA + stent group received nasobiliary drainage for 1 – 3 days after RFA to prevent blockage of the bile duct from tumor necrosis, and underwent an additional endoscopic retrograde cholangiopancreatography (ERCP) for stent placement. Rectal indomethacin (100 mg) was administered within the 30 minutes prior to ERCP to prevent the occurrence of postoperative pancreatitis in all patients.

Routine blood and liver function tests were conducted preoperatively, as well as at 2 weeks, and 1 and 3 months, postoperatively. Quality of life was assessed using the KPS every 3 months. All patients underwent stent replacement every 3 months or when they had recurrent jaundice or cholangitis symptoms. The thickness of the tumor mass was routinely measured by intraductal ultrasonography (IDUS) during each ERCP. If tumor thickness measured by IDUS in the RFA + stent group was more than 6 mm or increased from the previous ERCP, the patient underwent repeat RFA.


#

Radiofrequency ablation

Patients were placed in the prone or lateral position and received oxygen with electrocardiogram monitoring. Common bile duct cannulation was performed using a triple-lumen sphincterotome (KD-V411M-0725; Olympus Corp., Tokyo, Japan) combined with a guidewire (Boston Scientific, Marlborough, Massachusetts, USA). Cholangiography was performed to identify the main location of the stricture ([Fig. 1 a]). The length of the bile duct stricture and the thickness of the bile duct were confirmed by IDUS ([Fig. 1 b]). The radiofrequency ablation probe (Habib EndoHPB; EMcision, London, United Kingdom) was inserted into the bile duct along the guidewire. The bipolar RFA probe has two ring electrodes 8 mm apart, with the distal electrode 5 mm away from the leading edge. This provides an effective cylindrical ablation a 25 mm length between the distal and proximal electrode margins [19]. The electrode was placed in the bile duct stricture under radiographic fluoroscopy and connected to a 400 kHz radiofrequency generator (RITA 1500X; AngioDynamics, Latham, New York, USA). RFA was performed using a power of 7 – 10 W for 90 seconds, and the electrode was kept at the ablation site for an additional 1 minute to allow the RFA probe to cool before being moved, in order to prevent tearing off surrounding tumor tissue. If the stricture was more than 2.5 cm, step-by-step RFA was performed from the top to bottom ([Fig. 1 c, d]). After RFA, the bile duct was cleaned by balloon aspiration to remove residual necrotic tissue and debris ([Fig. 1 e]).

Zoom Image
Fig. 1 Radiofrequency ablation (RFA) and stent placement procedure. a Cholangiography was performed to identify the main location of the stricture. b The length of the bile duct stricture and the thickness of the bile duct were confirmed by intraductal ultrasonography. c,d RFA was performed step-by-step (arrows) using a power of 7 – 10 W for 90 seconds. e After RFA, the bile duct was cleaned by balloon aspiration to remove residual necrotic tissue and debris. f A biliary plastic stent was inserted to ensure adequate decompression and bile drainage.

#

Biliary stenting

An 8.5 Fr biliary plastic stent (Boston Scientific) was inserted via a standard ERCP procedure to ensure adequate decompression and bile drainage ([Fig. 1 f]). An appropriate stent length was selected according to the lengths of the stricture. Routine blood tests and liver function tests were measured in all patients preoperatively, and every month or when cholangitis symptoms were present postoperatively. The duration of stent patency of the two groups was recorded.


#

Intraductal ultrasonography

In order to assess the response to RFA treatment, IDUS was performed with a high-frequency probe for detecting anatomic changes to the wall of the bile duct [21]. After successful bile duct intubation in each ERCP, an ultrasound probe (20 MHz/6 Fr, transducer, UM G20 ± 29R; Olympus Co., Tokyo, Japan) was inserted into the common bile duct along the guidewire, and the length and diameter (mm) at the thickest part of the tumor stricture were measured by ultrasound (MAJ-935, EM1; Olympus).


#

Adverse events

Post-ERCP adverse events (including acute pancreatitis, bleeding, biliary infection, perforation, and any adverse outcomes requiring hospital admission or prolonged hospital stay for further management) were monitored. Severity of adverse events was graded according to the Cotton criteria [22]. The frequency and severity of postoperative adverse events and recovery time of the two groups were recorded.


#

Outcomes

The primary outcome of the study was the mean survival time, which was defined from the first RFA. All patients were followed up via telephone inquiries until the time of their death. The second outcome was stent patency and the incidence of post-ERCP adverse events.


#

Statistical analysis

Before initiation of the study, a biostatistician and one of the principal investigators (J.Y.) worked together to determine the power calculation for the study. The primary aim of the study was to investigate the effect of RFA on the survival time of patients with unresectable extrahepatic cholangiocarcinoma. According to previous studies, the mean survival time was 3.3 months [23] and 12.3 months [17] in the stent-only and RFA + stent groups, respectively [24]; the total duration of patient enrollment was 6 months, and the follow-up period was 18 months. Each group required a minimum sample size of 12 in order to identify a 20 % difference in survival time between groups, with 90 % power (P < 0.05), as per the sample size calculation formula used.

Categorical variables were analyzed using the chi-squared test, while continuous variables were analyzed using Student’s t test or nonparametric tests. Patient survival was compared using the Kaplan – Meier method. Factors known to influence survival in extrahepatic cholangiocarcinoma patients and variables found to be significantly different between the RFA + stent and stent-only groups, were included into the Cox regression model to determine parameters associated with survival in this study. Groups were also compared for general characteristics, stent patency period, and the rate of postoperative adverse events. P values of < 0.05 were considered statistically significant. All statistical analyses were performed using SPSS version 16.0 (SPSS, Chicago, Illinois, USA).

This study was approved by the Ethics Committee of Hangzhou First People’s Hospital and conducted in accordance with the Declaration of Helsinki. All patients enrolled in the study signed informed consent documents. All authors had access to the study data, and have reviewed and approved the final manuscript. This study was registered with ClinicalTrials.gov (NCT02592538).


#
#

Results

Patient characteristics

A total of 96 patients with obstructive jaundice were diagnosed with extrahepatic cholangiocarcinoma by pathology (88 cases by ERCP brush, 8 cases by EUS-guided fine-needle aspiration) during the period October 2015 – May 2016, and 68 patients were finally enrolled in the study ([Fig. 2]). Three patients (two in the RFA + stent group and one in the stent-only group) were lost to follow-up, and thus, 32 cases in the RFA + stent group and 33 cases in the stent-only group were included in the final analysis. There were no statistically significant differences in age, sex, body mass index, tumor stage and location, stricture length and bile duct wall thickness, and the time between diagnosis to treatment (with or without RFA) between the two groups ([Table 1]).

Zoom Image
Fig. 2 Study population flow chart.
Table 1

Patient characteristics, tumor location, and stages by group.

 

RFA + stent group (n = 32)

Stent-only group (n = 33)

P

Sex, male:female, n

15:17

18:15

0.54[1]

Age, mean ± SD, years

62.0 ± 7.7

64.5 ± 3.4

0.24[2]

Body mass index, mean ± SD, kg/m2

22.6 ± 2.5

23.0 ± 4.6

0.43[2]

Albumin at diagnosis, mean ± SD,

31.4 ± 7.3

32.2 ± 8.6

0.51[2]

Length of stricture, mean ± SD, mm

35.5 ± 5.2

36.9 ± 9.4

0.30[2]

Thickness of stricture, mean ± SD, mm

8.6 ± 3.6

8.0 ± 3.3

0.17[2]

Time from diagnosis to treatment, mean ± SD, days

3.8 ± 0.5

3.2 ± 0.4

0.47[2]

Tumor location, n

  • Bismuth type I-II hilar cholangiocarcinomas

10

9

0.72[1]

  • Distal

22

24

RFA, radiofrequency ablation.

1 Chi-squared test.


2 Unpaired t test.



#

Serum bilirubin

Preoperative total and direct serum bilirubin levels were significantly elevated and were not significantly different between the groups ( > 0.05). Postoperative bilirubin levels at 2 weeks were significantly reduced in the RFA + stent group when compared with those of the stent-only group. Postoperative bilirubin levels at 1 and 3 months were not significantly different between two groups (P > 0.05) ([Table 2]).

Table 2

Comparison of serum bilirubin between the two groups.

 

RFA + stent group (n = 32)

Stent-only group (n = 33)

P [*]

Total bilirubin, mean ± SD, µmol/L

 Preoperative

266.8 ± 88.5.

245.9 ± 76.2

0.23

  • After 2 weeks

106.8 ±51.5

196.8 ± 88.5

0.02

  • After 1 month

85.8 ± 15.1

102.8 ± 45.6

0.35

  • After 3 months

39.2 ± 6.3

46.9 ± 8.9

0.68

Direct bilirubin, mean ± SD, µmol/L

 Preoperative

188.5 ± 48.6

169.5 ± 58.4

0.43

  • After 2 weeks

69.8 ± 28.5

106.2 ± 83.5

0.03

  • After 1 month

56.9 ±8.9

68.5 ± 7.8

0.69

  • After 3 months

19.3 ± 5.9

22.6 ± 7.8

0.58

RFA, radiofrequency ablation.

* Unpaired t tests.



#

IDUS measurement

The mean length of stricture in the RFA + stent group was not significantly different from that in the stent-only group (35.5 ± 5.2 vs. 36.9 ± 9.4 mm; P = 0.30). Preoperative thickness of the stricture was not significantly different between the two groups (8.6 ± 3.6 vs. 8.0 ± 3.3 mm; P = 0.17). However, 3 months after treatment, the thickness of the stricture had significantly reduced in the RFA + stent group when compared with that of the stent-only group (6.3 ± 1.2 vs. 14.5 ± 3.3 mm; P = 0.01). At 6 months, the tumor mass in the RFA + stent group had thickened compared with measurement at 3 months, but continued to be significantly lower when compared with the stent-only group (11.3 ± 3.8 vs. 16.8 ± 4.8 mm; P = 0.03).


#

Stent patency period

There was no statistically significant difference in the stent length between the RFA + stent group and the stent-only group (8.3 ± 2.2 vs. 9.3 ± 2.9 cm; P > 0.05). Stent patency of the RFA + stent group was significantly longer than that of the stent-only group: 6.8 months (95 %CI 3.6 – 8.2) and 3.4 months (95 %CI 2.4 – 6.5), respectively (P = 0.02) ([Fig.3]).

Zoom Image
Fig. 3 Comparison of stent patency between the radiofrequency ablation (RFA) + stent group and the stent-only group. Stent patency of the RFA + stent group was significantly longer than that of the stent group: 6.8 months (95 %CI 3.6 – 8.2) and 3.4 months (95 %CI 2.4 – 6.5), respectively ( = 0.02).

#

KPS scores

Preoperative KPS scores between the two groups did not differ significantly (82.9 ± 9.3 vs. 79.9 ± 7.8;  = 0.28). However, postoperatively, the KPS scores of patients in the RFA + stent group were significantly higher when compared with those of the stent-only group, after 1 month (86.1 ± 6.8 vs. 72.4 ± 8.2; P = 0.02), 3 months (71.4 ± 7.1 vs. 60.3 ± 5.4;  = 0.04), 6 months (61.4 ± 7.1 vs. 48.2 ± 6.2; P = 0.03), and 9 months (58.2 ± 11.5 vs. 22.5 ± 8.9; P < 0.001) ([Fig. 4]).

Zoom Image
Fig. 4 Comparison of Karnofsky performance scores (KPS) between groups. KPS scores in the radiofrequency ablation (RFA) + stent group were statistically significantly higher than the stent group after 1, 3, 6, and 9 months postoperatively (P < 0.05).

#

Overall survival

All patients had died by July 2017. The total follow-up duration of the study was 21 months. The 6-month survival rate (96.9 % vs. 81.8 %) was not statistically different between the RFA + stent group and the stent-only group (P = 0.08). However, the survival rates at 9 months, 12 months, and 15 months in the RFA + stent group were all significantly higher than those in the stent-only group (87.5 % vs. 24.2 %, 62.5 % vs. 12.1 %, 28.1 % vs. 3.0 %, respectively; P < 0.05) ([Fig.5]). The overall mean survival time was also significantly longer in the RFA + stent group than the stent-only group (13.2 ± 0.6 months [95 %CI 11.8 – 14.2] vs. 8.3 ± 0.5 months [95 %CI 7.3 – 9.3]; P < 0.001) ([Fig.6]). Multivariable Cox regression analysis showed that RFA was the main protective factor affecting the survival of patients (hazard ratio 0.182, 95 %CI 0.08 – 0.322; P < 0.001).

Zoom Image
Fig. 5 Comparison of survival rate between the radiofrequency ablation (RFA) + stent group and the stent-only group. The 6-month survival rate (96.9 % vs. 81.8 %) was not statistically different between the RFA + stent group and the stent-only group (P = 0.08). The survival rates at 9, 12, and 15 months in the RFA + stent group were all significantly higher than those in the stent-only group (87.5 % vs. 24.2 %, 62.5 % vs. 12.1 %, 28.1 % vs. 3.0 %, respectively; P < 0.05).
Zoom Image
Fig. 6 Comparison of overall mean survival time between the radiofrequency ablation (RFA) + stent group and the stent-only group. The Kaplan – Meier survival curve shows that the overall mean survival time of the RFA + stent group was significantly longer than that of the stent-only group (13.2 ± 0.6 months, 95 %CI 11.8 – 14.2 vs. 8.3 ± 0.5 months, 95 %CI 7.3 – 9.3; P < 0.001).

#

Postoperative adverse events

Patients in the RFA + stent group underwent 125 ERCP procedures (mean number of ERCPs per patient 4.7). Patients in the stent-only group underwent 118 ERCPs (mean number of ERCPs per patient 3.8), and the difference was not statistically significant. In the RFA + stent group, 2 patients underwent one RFA, 13 patients underwent two, 13 patients underwent three, and 4 patients underwent four RFAs.

Adverse events of chills and fever occurred in two patients (6.3 %) in the RFA + stent group, and were diagnosed as acute cholangitis. Both patients improved after nasobiliary drainage through the bile duct and intravenous antibiotic therapy. There were three cases (9.1 %) of postoperative adverse events in the stent-only group, including one case of acute cholangitis, one case of acute pancreatitis, and one case of hemorrhage of the incision margin of the papilla. All were cured with endoscopic treatment. There was no significant difference between the two groups in the incidence of adverse events (P > 0.05). Neither group experienced serious adverse events, such as perforation, nor operation-related death.

Causes of death were metastases due to tumor progression (pulmonary, hepatic, peritoneal n = 29), sepsis due to cholangitis (n = 12), cachexia (n = 11), chronic renal failure (n = 8), cardiac failure (n = 5); there was no difference between two groups (P > 0.05) ([Table 3]).

Table 3

Comparison of advert event and cause of death between the two groups.

 

RFA + stent group (n = 32)

Stent-only group (n = 33)

P

Advert event, n (%)

 2 (6.3)

 3 (9.1)

0.67

  • Acute cholangitis

 2

 1

  • Acute pancreatitis

 0

 1

  • Hemorrhage of papilla

 0

 1

Cause of death

  • Metastases

11

18

0.10

  • Sepsis due to cholangitis

 7

 5

0.56

  • Cachexia

 6

 5

0.70

  • Chronic renal failure

 5

 3

0.42

  • Cardiac failure

 3

 2

0.62

RFA, radiofrequency ablation.


#
#

Discussion

This study showed that endoscopic biliary RFA can significantly alleviate jaundice, reduce the thickness of tumor lesions, prolong extrahepatic cholangiocarcinoma survival and stent patency, improve the quality of life, and does not increase the risk of complications. To our knowledge, this is the first study to use a prospective cohort design to explore the clinical efficacy and safety of RFA in the treatment of primary extrahepatic cholangiocarcinoma.

In the treatment of malignant tumors, RFA can induce high temperatures locally, which leads to coagulation necrosis of tumor cells and controls tumor re-growth [13]. Sharaiha et al. [25] reported on 69 patients with malignant biliary obstruction who were treated with RFA. The diameter of bile duct stricture increased from 2.02 ± 1.2 mm preoperation to 4.9 ± 2.1 mm postoperation (P < 0.001). The stent patency rate was 95.7 % (66 /69) 30 days after operation. Figueroa-Barojas et al. [26] also compared the diameter of bile duct stricture before and after RFA treatment in 25 patients with malignant biliary obstruction. The average diameter of bile duct stricture increased from 1.7 mm (0.5 – 3.4 mm) to 5.2 mm (2.6 – 9 mm), an average increase of 3.5 mm, and the stent patency rate was 100 % at 30 days postoperation. The results of these two studies show that RFA can restore patency of the bile duct, and the stent patency rate was more than 95 % 30 days after the operation. However, both studies had short follow-up times, lacking data on stent patency during long-term follow-up.

Alis et al. [27] reported on 10 patients with malignant biliary obstruction who underwent RFA therapy. The diameter of bile duct stricture increased from 1.5 to 5 mm, and the stent patency was 9 months in nine patients (range 6 – 15 months). Although the follow-up time was long, the sample size was small, and there was no control group.

In the current study, postoperative bilirubin levels at 2 weeks were significantly reduced in the RFA + stent group compared with the stent-only group, suggesting that RFA could alleviate jaundice more rapidly. Stent patency of the RFA + stent group was 6.8 months, which was significantly longer than that of the stent-only group. The thickness of tumor lesions measured with IDUS was clearly decreased in the RFA + stent group after 3 and 6 months postoperatively. Our study further confirmed that RFA induced prolonged stent patency, which may be attributed to an enlarged bile duct resulting from the effect of RFA on cholangiocarcinoma tissue.

There is currently insufficient evidence to show that RFA prolongs the survival of patients with extrahepatic cholangiocarcinoma. In a retrospective analysis by Dolak et al. [28] of 58 patients with bile duct obstruction who underwent 87 RFA procedures, the average postoperative survival was 10.6 months (95 %CI 6.9 – 14.4), but the study did not include a control group and was therefore insufficient to determine the effect of RFA on survival. Sharaiha et al. [29] conducted a retrospective analysis of 64 patients with malignant biliary strictures in 2014, and compared patient survival between those who underwent RFA plus metal stent implantation and those who received metal stent implantation only. The results showed that the average survival time of the two groups of patients was 5.9 months (4.6 – 14.1 months), and the log-rank analysis of the survival time between the two groups was not statistically significant (P = 0.87). Although the study included a control group, the results did not show that RFA prolonged patient survival. In the later Sharaiha et al. study [25], the authors further retrospectively reviewed 69 patients who underwent RFA + stent placement for malignant bile duct obstruction, including unresectable cholangiocarcinoma (n = 45), pancreatic cancer (n = 19), gallbladder carcinoma (n = 1), gastric cancer (n = 1), and liver metastasis of colon cancer (n = 3). Compared with the survival of patients who received stent-only treatment in the Surveillance, Epidemiology, and End Results database (the National Cancer Institute-supported national cancer surveillance program), the survival times of patients with pancreatic cancer (5.9 vs. 14.6 months; P < 0.001) and cholangiocarcinoma (6.2 vs. 17.7 months; P < 0.001) treated with RFA were both significantly improved. Although the study suggests that RFA can prolong the survival time of patients, the control group was based on historical data and, thus, is subject to selection bias. In addition, malignant obstruction was caused by various types of malignant tumors, and it is therefore difficult to accurately determine the effect of RFA on the survival of extrahepatic cholangiocarcinoma.

Kallis et al. [30] reported the data of 23 patients with biliary obstruction due to unresectable pancreatic cancer who underwent endoscopic RFA combined with implantation of a metallic stent, and compared them with 46 concurrent cases who only received a metallic stent after matching for age, sex, metastasis, and adverse events. The median survival of the RFA group was significantly higher than that of the control group (226 days [interquartile range 140 – 526] vs. 123.5 days [44 – 328]; P = 0.01]. Multivariate analysis showed that RFA was a major predictor of 90-day survival (odds ratio [OR] 21.07, 95 %CI 1.45 – 306.64; P = 0.03) and 180-day survival (OR 4.48, 95 %CI 1.04 – 19.30; P = 0.04). Although this study suggests that RFA can prolong survival in patients with malignant biliary obstruction, it was a retrospective case-control analysis and only included patients with pancreatic cancer. Therefore, while RFA has been shown to play a role in prolonging the survival time of patients with malignant biliary obstruction, it has yet to be elucidated whether RFA prolongs the survival of patients with primary extrahepatic cholangiocarcinoma.

The objective of the current study was to explore the impact of RFA therapy on the survival of patients with extrahepatic cholangiocarcinoma. All patients enrolled had extrahepatic cholangiocarcinoma. The results showed that, compared with the stent-only group, the RFA + stent group had significantly higher survival rates at 9, 12, and 15 months. Approximately 70 % of patients in the stent-only group died between 6 months and 9 months after surgery, while only 13 % of patients died in the RFA + stent group. The overall mean survival time in the RFA + stent group was significantly longer than that in the stent-only group, suggesting that RFA therapy can prolong the survival of patients with extrahepatic cholangiocarcinoma. This study provides powerful scientific evidence that RFA should be considered clinically for the treatment of extrahepatic cholangiocarcinoma.

There are still many concerns regarding RFA as a treatment for extrahepatic cholangiocarcinoma in clinical practice. First, there is no consensus on the optimal frequency and interval of RFA therapy. In most studies, RFA therapy was performed regularly every 3 – 4 months [16] [27] [28]. Because of individual differences in tumor growth rate, and thus stent obstruction, it is difficult to accurately determine the time and frequency of RFA treatment required for each patient. IDUS can clearly show changes in the structure of the bile duct wall. In the current study, patients in the RFA + stent group underwent IDUS to evaluate the thickness of the bile duct wall at each ERCP session, and RFA was repeated when IDUS showed a significant increase in tumor thickness. We suggest that the optimal time interval between RFA treatments is 6 months, as the thickness of the tumor mass was increased at 6 months postoperatively. Second, RFA acts only on local tumors, indicating that this treatment may not have the ability to completely destroy a tumor mass. Cisplatin and gemcitabine have been used as first-line chemotherapies in advanced cholangiocarcinoma [11]. However, the efficacy of RFA combined with palliative chemotherapy for the treatment of extrahepatic cholangiocarcinoma is not clear. In the current study, in order to explore the effect of RFA on the survival time in patients with extrahepatic cholangiocarcinoma, patients who underwent other treatments that may affect the clinical efficacy, such as chemotherapy or radiotherapy, were excluded. Thus, more randomized controlled trials are warranted to further clarify the efficacy and adverse events of RFA and systemic chemotherapy for the treatment of extrahepatic cholangiocarcinoma.

Several review articles have reported that the incidence of adverse events after RFA ranges from 5.6 % to 27.1 %, including postoperative pain, acute cholangitis, cholecystitis, hemorrhage, and acute pancreatitis, although all events were cured by symptomatic treatment with no reported deaths [13] [24] [31]. Zhou et al. [32] reported two cases of biliary perforation after percutaneous RFA treatment of malignant bile duct obstruction; both patients recovered after the placement of a biliary stent. The results of the current study showed that the incidence of postoperative adverse events in the RFA + stent group was not significantly different from that in the stent-only group, suggesting that RFA did not increase postoperative morbidity. Most RFA adverse events were associated with conventional ERCP and stent placement. There were two cases of postoperative cholangitis in the RFA group, which may be associated with poor drainage of the bile duct or stent as a result of tumor necrosis, and both recovered after another ERCP and stent replacement.

The following measures were taken in the study to prevent the occurrence of adverse events. 1) RFA was conducted with 7 – 10 W power for 90 seconds, as high temperatures from ablation may cause damage within the bile duct, leading to bile duct perforation. Animal experiments have shown that the diameter of the ablation area increases with increasing ablation power and prolonged time [33]. 2) Antibiotics were administered 1 hour before RFA in all patients, and patients with long strictures (> 3 cm) in the RFA + stent group received nasobiliary drainage for 1 – 3 days after the operation to prevent blockage of the bile duct from tumor necrosis, which may result in cholangitis. (3) Rectal indomethacin (100 mg) was administered within the 30 minutes prior to ERCP to prevent the occurrence of postoperative pancreatitis in all patients [34].

This study has several limitations. First, the study included a relatively small sample size and employed a nonmulticenter design. However, our preliminary results have demonstrated the clinical efficacy and safety of RFA, which could guide future applications in clinical settings. Second, patients with Bismuth type III and IV hilar cholangiocarcinoma were excluded from the study, as it was difficult to determine the length of stricture in the RFA procedure. Wang et al. [35] reported that percutaneous intraductal RFA combined with metal stent placement was a technically safe and feasible therapeutic option for palliative treatment of unresectable Bismuth types III and IV hilar cholangiocarcinoma. Third, based on availability, 8.5 Fr rather than 10 Fr plastic stents were used in the study, although self-expanding metal stents are currently recommended for extrahepatic cholangiocarcinoma patients with an expected survival time greater than 6 months [7]. Therefore, compared with placement of metal or 10 Fr plastic stents, patients in the stent-only group may have been at greater risk of subsequent stent obstruction and the need for repeated ERCP.

In summary, RFA combined with stent placement can prolong biliary tract patency and overall survival without increasing the incidence of adverse events in patients with extrahepatic cholangiocarcinoma, except Bismuth type III and IV hilar cholangiocarcinoma. RFA plus stent implantation is effective and safe for the treatment of extrahepatic cholangiocarcinoma, and this approach can be used in the palliative treatment of unresectable extrahepatic cholangiocarcinoma, except Bismuth type III and IV hilar cholangiocarcinoma. These results should be confirmed in a large multicenter study.


#
#

Competing interests

None.

Acknowledgments

We gratefully acknowledge the statistical support from Yunxian Yu in the Department of Epidemiology and Health Statistics, School of Public Health, Zhejiang University, Hangzhou, China.

This study was supported by grants from the Health Department of Zhejiang Provence (2016RCB015) and the Health and Family Commission of Hangzhou Municipality (2014Z01).

* These authors contributed equally to this work.



Corresponding author

Xiaofeng Zhang, MD
Department of Gastroenterology
Hangzhou First People’s Hospital
Nanjing Medical University
#261 Huansha Road
Hangzhou, 310006
Zhejiang Province
China   
Fax: +86-0571-56006872   


Zoom Image
Fig. 1 Radiofrequency ablation (RFA) and stent placement procedure. a Cholangiography was performed to identify the main location of the stricture. b The length of the bile duct stricture and the thickness of the bile duct were confirmed by intraductal ultrasonography. c,d RFA was performed step-by-step (arrows) using a power of 7 – 10 W for 90 seconds. e After RFA, the bile duct was cleaned by balloon aspiration to remove residual necrotic tissue and debris. f A biliary plastic stent was inserted to ensure adequate decompression and bile drainage.
Zoom Image
Fig. 2 Study population flow chart.
Zoom Image
Fig. 3 Comparison of stent patency between the radiofrequency ablation (RFA) + stent group and the stent-only group. Stent patency of the RFA + stent group was significantly longer than that of the stent group: 6.8 months (95 %CI 3.6 – 8.2) and 3.4 months (95 %CI 2.4 – 6.5), respectively ( = 0.02).
Zoom Image
Fig. 4 Comparison of Karnofsky performance scores (KPS) between groups. KPS scores in the radiofrequency ablation (RFA) + stent group were statistically significantly higher than the stent group after 1, 3, 6, and 9 months postoperatively (P < 0.05).
Zoom Image
Fig. 5 Comparison of survival rate between the radiofrequency ablation (RFA) + stent group and the stent-only group. The 6-month survival rate (96.9 % vs. 81.8 %) was not statistically different between the RFA + stent group and the stent-only group (P = 0.08). The survival rates at 9, 12, and 15 months in the RFA + stent group were all significantly higher than those in the stent-only group (87.5 % vs. 24.2 %, 62.5 % vs. 12.1 %, 28.1 % vs. 3.0 %, respectively; P < 0.05).
Zoom Image
Fig. 6 Comparison of overall mean survival time between the radiofrequency ablation (RFA) + stent group and the stent-only group. The Kaplan – Meier survival curve shows that the overall mean survival time of the RFA + stent group was significantly longer than that of the stent-only group (13.2 ± 0.6 months, 95 %CI 11.8 – 14.2 vs. 8.3 ± 0.5 months, 95 %CI 7.3 – 9.3; P < 0.001).