Surgical Endoscopy (2022) 36:5559–5570 and Other Interventional Techniques

https://doi.org/10.1007/s00464-022-09181-2

REVIEW ARTICLE

Local palliative therapies for unresectable malignant biliary

obstruction: radiofrequency ablation combined with stent or biliary
stent alone? An updated meta‑analysis of nineteen trials
Shaoming Song1,2,3 · Haojie Jin1,3 · Qinghao Cheng2 · Shiyi Gong2 · Kun Lv1 · Ting Lei1,3 · Hongwei Tian1,2,4 ·
Xiaofei Li2 · Caining Lei2 · Wenwen Yang1,3 · Kehu Yang3,5 · Tiankang Guo1

Received: 14 August 2021 / Accepted: 27 February 2022 / Published online: 16 March 2022
© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022

Abstract
Background Recently, there has been a burgeoning interest in radiofrequency ablation combined with stent (RFA + Stent)
for unresectable malignant biliary obstruction (MBO). This study aimed to perform a meta-analysis to evaluate the efficacy
and safety of RFA + Stent compared with biliary stent alone.
Methods We searched PubMed, Cochrane Library, Embase, and Web of Science databases from their inception dates to June
20, 2021, for studies that compared RFA + Stent and stent alone for unresectable MBO. The main outcomes were survival,
patency, and adverse effects. All meta-analyses were calculated using the random-effects model.
Results A total of 19 studies involving 1946 patients were included in this study. Compared with stent alone, RFA + Stent
was significantly associated with better overall survival (HR 0.55; 95% CI 0.48, 0.63; P < 0.00001), longer mean survival
time (SMD 2.20; 95% CI 1.17, 3.22; P < 0.0001), longer mean stent patency time (SMD 1.37; 95% CI 0.47, 2.26; P = 0.003),
higher stent patency at 6 months (OR 2.82; 95% CI 1.54, 5.18; P = 0.0008). The two interventions had similar incidence of
postoperative abdominal pain (OR 1.29; 95% CI 0.94, 1.78; P = 0.11), mild bleeding (OR 1.28; 95% CI 0.65, 2.54; P = 0.48),
cholangitis (OR 1.09; 95% CI 0.76, 1.55; P = 0.65), pancreatitis (OR 1.39; 95% CI 0.82, 2.38; P = 0.22). Furthermore, the
serum bilirubin levels and stricture diameter after operations were significantly alleviated than before operations, but the
degree of alleviation between the two groups were not significantly different (all P > 0.05).
Conclusion Although the alleviation of serum bilirubin and stricture diameter did not differ between the two interventions,
RFA + Stent can significantly improve the survival and stent patency with comparable procedure-related adverse events than
stent alone. Thus, RFA + Stent should be recommended as an attractive alternative to biliary stent alone for patients with
unresectable MBO.

Keywords Radiofrequency ablation · Biliary stent · Malignant biliary obstruction · Meta-analysis

Abbreviations
CI Confidence interval
GRADE Grading of recommendations assessment,
development, and evaluation
Shaoming Song, Haojie Jin, and Qinghao Cheng contributed
equally to this article.

3
* Kehu Yang Evidence‑Based Medicine Center, School of Basic Medical
kehuyangebm2020@163.com Sciences, Lanzhou University, 199 West Donggang R.D.,
Lanzhou 730000, China
* Tiankang Guo
4
tiankangguo2019@163.com Key Laboratory of Molecular Diagnosis and Precision
Therapy of Surgical Tumors of Gansu Province, Lanzhou,
1
Department of Clinical Medicine, The First Clinical Medical China
College of Lanzhou University, 199 West Donggang R.D., 5
Key Laboratory of Evidence-Based Medicine and Knowledge
Lanzhou 730000, China
Translation of Gansu Province, Lanzhou, China
2
Department of General Surgery, Gansu Provincial Hospital,
Lanzhou, China

13
Vol.:(0123456789)
5560
HR Hazard ratio
I2  I-Squared
MBO Malignant biliary obstruction
NOS Newcastle–Ottawa Scale
OR Odds ratio
PRISMA Preferred reporting items for systematic
review and meta-analysis
RCTs Randomized controlled studies
RFA + Stent Radiofrequency ablation combined with
stent
ROB-2 The revised cochrane risk of bias tool
SMD Standardized mean differences
Malignant biliary obstruction (MBO) is a biliary system dis-
ease caused by various cancers such as cholangiocarcinoma,
pancreatic cancer, gallbladder carcinoma, ampullary cancer,
and so on [1, 2]. For patients with MBO at an early stage,
radical surgical resection can be conducted for potential
chances of cure. However, due to lack of specific symptoms
and signs, most patients with MBO were diagnosed at an
advanced stage [1, 3]. Biliary stent placement is currently
the standard treatment for these patients, which can alleviate
cholestasis and obstructive jaundice and improve liver func-
tion [4–6]. However, patients treated with biliary stent alone
had limited survival benefits. The median survival time was
only 8–9 months, and biliary stents frequently occluded,
especially in plastic or uncovered metal stents [6–9].
Recently, endoscopic radiofrequency ablation com-
bined with biliary stent placement (RFA + Stent) has been
introduced for patients with unresectable MBO [9–12].
As a new minimally invasive therapy, its frictional heat
effect induced by neighboring bipolar electrodes can lead
to hyperthermia and coagulation necrosis of local tumor
tissue [12, 13]. Some studies have proved the feasibil-
ity and safety in several malignant solid tumors such as
hepatocellular carcinoma, lung cancer, breast cancer, and
so on [14, 15]. However, regarding RFA for unresectable
MBO, current studies reported inconsistent results. In the
three related randomized controlled studies (RCTs), Gao
et al. [9]and Yang et al. [11] suggested that RFA + Stent
seemed to demonstrate better overall survival than stent
alone (P < 0.001 and P < 0.001; respectively), whereas
non-significant difference (P = 0.281) between two groups
was reported in the RCT by Kang et al. [12]. These studies
have also reported conflicting results about the endpoints
of mean stent patency time and stent rates [9, 11, 12].
Furthermore, during RFA treatment, there might be some
adverse events to the wall of the bile duct or the adjacent
vessels due to the potential thermal injury, such as bile
duct and intestinal perforation, severe bleeding, and so on
[4, 9, 10, 16]. Given the procedure-related adverse events
and high cost of RFA therapy, it is necessary to determine
13
Surgical Endoscopy (2022) 36:5559–5570
the specific benefit-risk profiles of RFA for patients with
unresectable MBO.
High-quality evidence requires constant updating [17].
Compared with previous meta-analyses, many studies,
including three RCTs, have been published and added to
the evidence of more endpoints [18]. Therefore, an updated
meta-analysis was performed to investigate the efficacy and
safety between RFA + Stent and stent alone for patients with
unresectable MBO.
Materials and methods
This meta-analysis was performed according to Cochrane
Handbook version 6.2 [19] and Preferred Reporting Items
for Systematic Review and Meta-Analysis (PRISMA) guide-
line [20]. The protocol of this study was registered in PROS-
PERO (CRD42021259047).
Literature search
PubMed, Cochrane Library, Web of Science, and Embase
databases were searched to identify potential eligible stud-
ies from inception to Jun 20, 2021. We used the following
MeSH terms and free-text terms: "Stent," "Radiofrequency
Ablation," and "Malignant Biliary Obstruction (Gallbladder
Neoplasms, Cholangiocarcinoma, Pancreatic Neoplasms,
or Ampulla of Vater cancer)." We also manually cross-
checked the list of references in relevant articles. There were
no regional and language restrictions, but it was limited to
human studies. The detailed search strategies were presented
in Appendix 1.
Inclusion and exclusion criteria
The following inclusion criteria were considered in this
study:
(1) Population: patient with unresectable MBO (cholangio-
carcinoma, gallbladder carcinoma, pancreatic cancer,
ampullary cancer, and so on);
(2) Intervention and Comparison: RFA combined with
stent and biliary stent alone;
(3) Outcomes: overall survival, stent patency, the allevia-
tion of bilirubin and stricture diameter, and procedure-
related adverse events;
(4) Study design: RCTs and non-RCTs (cohort studies,
case–control studies, and historical controlled studies).
As a part of palliative treatment, this study allowed
patients to be treated with other nonsurgical anti-tumor ther-
apies such as chemotherapy, radiotherapy, immunotherapy,
and targeted therapy. However, in the number of patients
Surgical Endoscopy (2022) 36:5559–5570
with such treatments, the difference between the RFA + Stent
and stent alone groups must be non-significant (P > 0.05).
We also excluded non-comparable studies, letters, editorial,
case reports, reviews, and expert opinion. For duplicate data,
we included the most recent comprehensive study.
Assessment of studies quality
The revised Cochrane Risk of Bias Tool (RoB-2) was per-
formed to assess the risk of bias for each RCT [21]. Two
reviewers independently analyzed the five domains, includ-
ing randomization process, deviations from intended inter-
ventions, missing outcome data, measurement of the out-
come, and selection of the reported results. Each endpoint of
RCTs was classed as high risk, low risk, or some concerns.
The Newcastle–Ottawa Scale (NOS) was used to assess
the risk of bias for non-RCTs [22]. Each study was given
a score according to the nine items of this scale. Then each
study was considered a high-quality study (score = 8–9),
medium-quality study (score = 6–7), and low-quality study
(score < 6).
The quality of the evidence for each outcome was
assessed by GRADE principles (Grading of Recommenda-
tions Assessment, Development, and Evaluation) [23]. In
each outcome, the evidence's high, moderate, low, or very
low quality was evaluated according to five lower domains
(risk of bias, inconsistency, indirectness, imprecision, and
publication bias).
Data extraction and outcome definitions
Two reviewers independently analyzed eligible studies and
extracted the following data: first author, publication year,
country, study design, baseline characteristics, stent route,
stent material, treatment regimen (energy and time), overall
survival, mean survival time, mean stent patency time, stent
patency rates, the alleviation of serum bilirubin and stricture
diameter, and procedure-related adverse events (abdominal
pain, mild bleeding, cholangitis, and pancreatitis). When
relevant hazard ratio (HR) was not directly available, we
considered the data from Kaplan–Meier curves [24]. Also,
the medians with their ranges were converted into sample
means and standard deviations to keep the data consistent
for meta-analyses [25, 26].
The period from stent insertion to stent occlusion was
considered stent patency. Stent occlusion was diagnosed
by the imaging findings of increased proximal biliary duct
dilation combined with the presence of lumen oblitera-
tion in the stent [9]. Abdominal pain was diagnosed by the
presence of new or worsened abdominal pain. Hemoglobin
level decreased by < 3 g/dL, and no need for transfusion
after operations was defined as mild bleeding [12]. The
patients with elevated infectious indicators and the presence
5561
of fever (> 38 °C for 24–48 h after operations) combined
with elevated cholestatic parameters were considered chol-
angitis [27]. Pancreatitis was defined as the serum amylase
level higher than the standard limit of three times or more
at > 24 h after the operations, combined with the presence
of new or worsened abdominal pain [12].
Statistical analysis
All meta-analyses were performed by Review Manager 5.3
and Stata 14.0. The dichotomous variables were assessed by
odds ratio (OR) and their 95% confidence interval (CI), con-
tinuous variables by standardized mean difference (SMD),
and overall survival by HR. All pooled results were calcu-
lated using the random-effect model. The chi-squared (χ2)
test and I-squared (I2) were calculated to evaluate the het-
erogeneity. When high heterogeneity (P < 0.1 or I2 > 50%)
was reported, we prioritized clinical and methodological
heterogeneities. P < 0.05 was considered to be statistically
significant. We also performed analyses of sensitivity and
publication bias to explore heterogeneity between studies
and to verify the stability of the results. Furthermore, sub-
group analyses were conducted to provide more evidence
according to several variables.
Results
Study selection
We identified 703 articles from the databases (90 from Pub-
Med, 391 from Embase, 36 from Cochrane Library, and 186
from Web of Science). After removing duplicates (205 stud-
ies), the total number of studies was 498. Of these, 450 were
excluded by assessing titles and abstracts, and the remain-
ing 48 studies underwent full-text evaluation. Ultimately,
19 eligible articles were included in this meta-analysis. The
PRISMA flowchart of the literature search was presented
in Fig. 1.
Study characteristics and quality assessment
The 19 eligible studies (including 3 RCTs [9, 11, 12], and
16 retrospective studies [27–42]) compared a total of 1946
patients (764 undergoing RFA + Stent and 1182 undergo-
ing stent alone). For primary tumor sites, 59.82% of these
patients were diagnosed with cholangiocarcinoma, 20.4%
patients with pancreatic cancer, and the remaining 19.78%
patients with other cancers. For stent materials, 66.08%
of these patients were treated with metal stents (most of
them were uncovered), 30.52% patients with plastic stents,
and the data of the remaining 3.4% were not available. One
study was published before 2015 [28], and 18 studies were
13
5562
Fig. 1  PRISMA flowchart of
literature selection
published from 2015 to 2021. The detailed baseline charac-
teristics of eligible studies were shown in Table 1.
For the three RCTs, two studies were considered at low
risk of bias, and one study was classified as having some
concerns for risk of bias e due to deviations from the
intended interventions (Table S1). For the 16 non-RCTs,
12 studies were evaluated as high-quality (score = 8–9), and
the remaining 4 studies [32, 33, 36, 39] were evaluated as
medium-quality (score = 6–7) (Table S1). Also, the GRADE
quality assessment for all outcomes was shown in Table S2.
Meta‑analysis
Overall survival
Fifteen eligible studies (including three RCTs and twelve
non-RCTs) investigated overall survival between the
RFA + Stent and stent alone groups (Fig. 2). The pooled
analysis showed that the RFA + Stent group had better over-
all survival than the stent alone (HR 0.55; 95% CI 0.48, 0.63;
P < 0.00001; I2 = 2%). In the subgroup analysis according
to different study designs, similar results were found in the
RCTs (HR 0.41; 95% CI 0.22, 0.75; P = 0.004) and the non-
RCTs subgroups (HR 0.58; 95% CI 0.50, 0.67; P < 0.00001).
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Surgical Endoscopy (2022) 36:5559–5570
Mean survival time
Mean survival time was compared in eleven eligible stud-
ies (including three RCTs and eight non-RCTs) (Table 2).
Compared with stent alone, the RFA + Stent group was
significantly associated with longer mean survival (SMD
2.20; 95% CI 1.17, 3.22; P < 0.0001). The subgroup analy-
sis reported similar results in the RCTs (SMD 5.03; 95%
CI 0.94, 9.12; P = 0.02) and the non-RCTs (SMD 1.34;
95% CI 0.38, 2.30; P = 0.006).
Mean stent patency time
Ten eligible studies (including three RCTs and seven
non-RCTs) evaluated mean stent patency between the
RFA + Stent and stent alone groups (Table 2). The pooled
analysis showed that the RFA + Stent group seemed to
demonstrate longer mean stent patency time than the
stent alone (SMD 1.37; 95% CI 0.47, 2.26; P = 0.003). In
the subgroup analysis, similar results were found in the
non-RCTs (SMD 1.62; 95% CI 0.92, 2.32; P < 0.00001),
whereas there was no significant difference between the
two groups in the RCTs (SMD 0.61; 95% CI -1.85, 3.06;
P = 0.63).
 Table 1  Baseline characteristics of the included studies
Study Year Country Design Simple size Age Stent route Stent material Follow-up Outcomes
Total (E/C) (months)
RFA + Stent Stent alone

Sharaiha [28] 2014 USA Prospective 66 (26/40) 65 ± ­13a 66 + ­12a ERCP Metal/Plastic 29 (3–229)c ①⑥⑨⑫
Kallis [29] 2015 UK Retrospective 69 (23/46) 69 ± ­9a 70 ± ­10a ERCP Uncovered SEMS Until death ①②④⑤
Surgical Endoscopy (2022) 36:5559–5570

Li [30] 2015 China Retrospective 26 (12/14) 53b 60b PTC Uncovered SEMS NA ④⑤⑦⑧⑪
Liang [31] 2015 China Retrospective 76 (34/42) 67.5 ± 2.1a 63.1 ± 1.6a ERCP Uncovered/covered 11.3 ± 0.34a ①③④⑨⑪⑫
Kadayifci [32] 2016 USA Retrospective 50 (25/25) 65.4 ± 13.1a 62.4 ± 11.7a ERCP Plastic 9.4 (0.53–29.8)d ③④⑨⑩
Liu [33] 2016 China Retrospective 34 (19/15) 64b 63b PTC Uncovered SEMS NA ④⑤⑪
Wang [34] 2016 China Retrospective 36 (18/18) 56.6 ± ­12a 58.3 ± 10.7a PTC Uncovered SEMS Until death ①②③④⑤⑥⑪
Cui [35] 2017 China Retrospective 89 (50/39) 62 (55–69)c 68 (60–76)c PTC Uncovered SEMS 6b ①②③⑨⑩⑪⑫
Dutta [36] 2017 UK Retrospective 31 (15/16) 78b 76b ERCP Uncovered/covered NA ①⑪⑫
Wu [37] 2017 China Retrospective 71 (35/36) 58 (45–75)d 57 (38–73)d PTC Uncovered/covered 7.67 ± 2.86a ①②③⑤⑥⑨⑩⑪
Yang [11] 2018 China RCT​ 65 (32/33) 62 ± 7.7a 64.5 ± 3.4a ERCP Plastic 21 ①②③⑦⑧⑩⑪⑫
Bokemeyer [38] 2019 Germany Retrospective 42 (20/22) 68 ± ­2a 66a ERCP Plastic NA ①②
Gao [9] 2020 China RCT​ 174 (87/87) 68.5 ± 11.2a 67.9 ± 10.4a ERCP Plastic 31.8 (17.7–46)e ①②③④⑤⑨⑩⑪⑫
Orozco [39] 2020 México Prospective 40 (12/28) 56 ± ­9a 60 ± ­10a ERCP Metal/Plastic NA ①⑨
Yu [40] 2020 China Retrospective 70 (28/42) 64.5b 64b PTC Uncovered SEMS 8.2 ± 0.5a ①②③④⑤⑦⑨⑪
Kang [12] 2021 Korea RCT​ 48 (24/24) 73 (59–76)c 67 (59–73)c ERCP/PTC Uncovered SEMS 3.95 (2.85–8.5)d ①②③④⑤⑪⑫
Kong [41] 2021 China Retrospective 277 (150/127) 62 (28–87)d 59 (34/82)d PTC Uncovered SEMS 10.7 ± 3.4a ②③⑨⑩⑪⑫
Uyanik [27] 2021 Turkey Retrospective 62 (30/32) 67.8 ± 12.1a 65 ± 7.2a PTC Uncovered SEMS 7 (2–11)d ①④⑤⑥⑨⑩⑪
Xia [42] 2021 China Retrospective 620(124/496) 68 ± 12.2a 67 ± 11.5a ERCP Metal/Plastic NA ①②⑩⑪⑫

RFA radiofrequency ablation, RCT​ randomized controlled trial, RS retrospective study, PS prospective study, Total (E/C) total (experimental group/ control group), NA not available, ERCP
endoscopic retrograde cholangiopancreatography, PTC percutaneous transhepatic cholangiography, SEMS self-expandable metallic stent, ① overall survival, ② mean survival time, ③ mean stent
patency time, ④ stent patency rate at 3 months, ⑤ stent patency rate at 6 months, ⑥ alleviation of stricture diameter, ⑦ alleviation of total bilirubin, ⑧ alleviation of direct bilirubin, ⑨ abdominal
pain, ⑩ mild bleeding, ⑪ cholangitis, ⑫ pancreatitis
a
Mean and standard deviation
b
Median
c
Median with their interquartile range
d
Median with their range
e
Median with their 95% CI

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5563
5564
Fig. 2  Forest plot comparing RFA + Stent vs Stent alone regarding overall survival
Stent patency rates
Nine studies (including two RCTs and seven non-RCTs)
evaluated the stent patency rate at 3 months (Table 2).
The pooled analysis did not show any significant differ-
ence between the two groups (OR 1.20; 95% CI 0.68,
2.13; P = 0.52; I 2 = 27%). The subgroup analysis also
reported similar results in the RCTs (OR 0.70; 95% CI
0.40, 1.22; P = 0.21) and the non-RCTs (OR 1.82; 95%
CI 0.94, 3.55; P = 0.08).
Furthermore, the stent patency rate at 6 months also
was investigated in nine studies (including two RCTs and
seven non-RCTs) (Table 2). The pooled results showed
the RFA + Stent group had a significantly higher stent
patency rate than the stent alone (OR 2.82; 95% CI 1.54,
5.18; P = 0.0008). In the subgroup analysis, similar
results were found in the non-RCTs (OR 3.95; 95% CI
2.14, 7.27; P < 0.0001), whereas there was no significant
difference between the two groups in the RCTs (OR 1.17;
95% CI 0.62, 2.23; P = 0.63).
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Surgical Endoscopy (2022) 36:5559–5570
Alleviation of stricture diameter and serum bilirubin
The degree of alleviation of stricture diameter and serum
bilirubin were compared in four and three studies, respec-
tively (Table 2). The pooled analyses showed there were no
significant differences between the two groups (all P > 0.05),
and low heterogeneities were found in these analyses (all
I2 < 50%).
Procedure‑related adverse events
Between the RFA + Stent and Stent alone groups, the pooled
analyses showed no significant differences were found in
postoperative abdominal pain (OR 1.29; 95% CI 0.94, 1.78;
P = 0.11; I2 = 0%), mild bleeding (OR 1.28; 95% CI 0.65,
2.54; P = 0.48; I2 = 22%), cholangitis (OR 1.09; 95% CI
0.76, 1.55; P = 0.65; I2 = 0%) (Fig. 3), pancreatitis (OR 1.39;
95% CI 0.82, 2.38; P = 0.22; I2 = 0%) (Table 2). In the sub-
group analyses, similar results were observed in the RCTs
Surgical Endoscopy (2022) 36:5559–5570 5565

and non-RCTs (all P > 0.05), and low heterogeneities (all

98%
97%
27%
58%

22%
0%
0%
0%
0%

0%
0%
I2 < 50%) in these analyses.
I2

< 0.0001

0.0008
0.003
0.52

0.77
0.15
0.37
0.11
0.48
0.65
0.22
Subgroup analysis
P

We performed subgroup analyses of overall survival and

S/P studies and participants, RCTs randomized controlled trials, SMD standard mean difference, OR odds ratio, 95% CI 95% confidence intervals, P P value, I2 I-squared test
cholangitis according to the following variables: data
SMD/OR (95% CI)

0.04 [− 0.22, 0.30]

0.23 [− 0.08, 0.55]
0.14 [− 0.17, 0.46]
2.20 [1.17, 3.22]
1.37 [0.47, 2.26]
1.20 [0.68, 2.13]
2.82 [1.54, 5.18]

1.29 [0.94, 1.78]

1.28 [0.65, 2.54]
1.09 [0.76, 1.55]
1.39 [0.82, 2.38]
sources, stent routes, stent materials, primary tumor sites,
and additional nonsurgical anti-tumor treatments. The
recalculated results were in keeping with the original meta-
All included studies

analysis (Table 3). Moreover, we also performed a subgroup

analysis of mean stent patency time based on different bil-
iary stent materials (Fig. S1). The results showed that longer
11/1561

14/1666
10/956

10/962
8/1395

9/1446
9/569
9/577
4/235
3/161
3/161

stent patency time from RFA + Stent (SMD 1.70; 95% CI

S/P

0.86, 2.54; P < 0.0001 I2 = 93%) was found in the uncov-

ered metal stent subgroup, whereas there was no signifi-
98%
92%
0%
38%
0%
0%
41%
0%
16%
0%
0%

cant difference between the two interventions in the plastic

I2

stent subgroup (SMD 0.63; 95% CI − 1.83, 3.09; P = 0.61;

< 0.0001

< 0.0001
0.006

I2 = 99%). However, due to the small sample size and high

0.08

0.77
0.81
0.52
0.16
0.16
0.83
0.05

heterogeneity in some subgroups, these results should be

P

considered carefully.
SMD/OR (95% CI)

0.04 [− 0.22, 0.30]

0.05 [− 0.36, 0.46]
0.19 [− 0.39, 0.77]
1.34 [0.38, 2.30]
1.62 [0.92, 2.32]
1.82 [0.94, 3.55]
3.95 [2.14, 7.27]

1.26 [0.91, 1.75]

1.60 [0.83, 3.08]
1.04 [0.70, 1.55]
1.81 [0.99, 3.30]

Heterogeneity analysis

High heterogeneities were reported in endpoints of mean

survival time and mean stent patency time (I2 = 98% and
I2 = 97%; respectively). In response, we prioritized the clini-
Non-RCTs

cal, methodological, or statistical heterogeneities. By care-

11/1379
8/1274

6/1156

6/1159
7/669
7/347
7/355
4/235

9/788

fully reading the full texts, we found that the median fol-
2/96
2/96
S/P

low-up periods were only 135 days (RFA + Stent group) and
119.5 days (stent alone group) in the study by Kang et al.,
99%
98%
0%
0%

0%
0%
0%

which may fail to demonstrate the benefits from RFA + Stent

I2

–
–
–
–

treatment in survival and stent patency time. Furthermore,

0.02
0.63
0.21
0.63

0.05
0.53
0.31
0.24
0.54
0.30

we found that plastic stent was used after RFA in the study
–
P

by Gao et al. which may affect stent patency greatly. How-

SMD/OR (95% CI)

0.61 [− 1.85, 3.06]

0.16 [− 0.33, 0.64]

ever, the recalculated results were not significantly altered

5.03 [0.94, 9.12]

0.70 [0.40, 1.22]

1.17 [0.62, 2.23]

0.50 [0.01, 1.00]

2.07 [0.50, 8.57]

0.33 [0.05, 2.12]
1.31 [0.55, 3.08]
0.54 [0.17, 1.71]

The pooled results of this outcome were calculated by SMD

after excluding the two studies by sensitivity analyses or

The pooled results of this outcome were calculated by OR

performing subgroup analyses. There were still high het-

erogeneities in the two endpoints (all I2 ≥ 90%). Thus, these
studies should not be considered as the sources of heteroge-
–

neities. We speculated that the high heterogeneities might

be caused by the large range of these continuous data among
3/287
3/287
2/222
2/222

1/174
2/239
3/287
3/287
RCTs
Table 2  Pooled results of other outcomes

1/65
1/65
S/P

eligible studies.
–
Alleviation of stricture ­diametera
­ onthsb
­ onthsb

Alleviation of direct b­ ilirubina

Sensitivity analysis and publication bias

Alleviation of total ­bilirubina
Mean stent patency t­imea
Stent patency rate at 3 m
Stent patency rate at 6 m

Sensitivity analyses were performed by eliminating one

Mean survival ­timea

study in each turn, removing medium-quality studies, or

Abdominal ­painb

changing the effects models. These recalculated results of

Mild ­bleedingb

Pancreatitisb
Cholangitisb

all endpoints did not be significantly changed. Furthermore,

Outcome

the funnel plots and egger's tests were performed to assess

the publication bias of overall survival, mean survival time,
b
a

13
5566 Surgical Endoscopy (2022) 36:5559–5570

Fig. 3  Forest plot comparing RFA + Stent vs Stent alone regarding cholangitis

Table 3  Pooled results of subgroup analyses

Variables Overall survival Cholangitis
S/P HR (95% CI) P I2 S/P OR (95% CI) P I2

Total 15/1546 0.55 [0.48, 0.63] < 0.00001 2% 14/1666 1.09 [0.76, 1.55] 0.65 0%
Data sources
Data from the originals 7/1100 0.51 [0.41, 0.63] < 0.00001 35% 14/1666 1.09 [0.76, 1.55] 0.65 0%
Data from other sources* 8/446 0.63 [0.49, 0.82] 0.0004 0% – – – –
Whether additional nonsurgical anti-tumor therapies were treated
Yes 13/1450 0.57 [0.50, 0.66] < 0.00001 0% 10/1510 1.01 [0.69, 1.47] 0.97 0%
Not 2/96 0.25 [0.12, 0.49] < 0.0001 16% 4/156 2.09 [0.69, 6.34] 0.19 0%
Primary tumor sites
Cholangiocarcinoma only 5/620 0.57 [0.38, 0.84] 0.005 53% 3/199 0.75 [0.17, 3.38] 0.71 0%
All cancers 10/926 0.60 [0.51, 0.70] < 0.00001 0% 9/1467 1.11 [0.77, 1.61] 0.58 0%
Treatment routes
ERCP 9/1183 0.53 [0.42, 0.66] < 0.00001 35% 5/966 0.84 [0.48, 1.47] 0.54 0%
PTC 5/315 0.59 [0.46, 0.75] < 0.0001 0% 8/652 1.28 [0.80, 2.05] 0.31 0%
Stent materials
Plastic 3/281 0.42 [0.21, 0.84] 0.01 69% 2/239 1.22 [0.50, 2.98] 0.66 0%
Uncovered Metal 7/432 0.58 [0.50, 0.67] < 0.00001 0% 9/700 1.30 [0.82, 2.08] 0.27 0%
Unclear 5/833 0.55 [0.45, 0.68] < 0.00001 0% 3/727 0.65 [0.32, 1.34] 0.25 0%

S/P studies/patients, HR hazard ratio, OR odds ratio, 95% CI 95% confidence intervals, P P value, I2 I-squared test, ERCP endoscopic retrograde
cholangiopancreatography, PTC percutaneous transhepatic cholangiography
*Data from Kaplan–Meier curves

13
Surgical Endoscopy (2022) 36:5559–5570
mean stent patency time, abdominal pain, and cholangitis.
Fig. S2 indicated there was no remarkable publication bias.
Discussion
Treatment option for unresectable MBO is still a matter
of debate. This study compared the efficacy and safety of
RFA + Stent and stent alone for patients with unresectable
MBO. In summary, treatment with RFA + Stent was associ-
ated with better clinical survival, longer stent patency time,
and better stent patency rate at 6 months compared with
stent alone. Furthermore, the two interventions had similar
efficacy in alleviating stricture diameter and serum biliru-
bin and had similar incidences of procedure-related adverse
events (abdominal pain, mild bleeding, cholangitis, and
pancreatitis).
Other meta-analyses had investigated comparative
efficacy and safety between RFA + Stent and sent alone
for patients with unresectable MBO. One suggested that
RFA + Stent was associated with improved stent patency
and survival time [18]. However, it included two abstracts
for these pooled results, and seven of eight eligible studies
were retrospective design. The other meta-analysis indicated
endoscopic RFA + Stent is effective and safe for patients
with unresectable MBO [43]. However, almost all eligible
studies were retrospectively designed case series, which viti-
ate the study's quality.
In our study, the pooled results showed the possibility
of an association of RFA + Stent with increased survival in
unresectable MBO patients, and it reached statistical sig-
nificance. The results were consistent with previous meta-
analyses and most of the included studies [18, 43]. The rel-
evant RCTs also proved similar results besides the study
by Kang et al. [9, 11, 12]. Kang et al. suggested that the
median survival time was not significantly different between
the groups (244 vs. 180 days, P = 0.281) [12]. As a local
palliative therapy, RFA can directly destroy tumor tissues by
frictional heat effect to slow tumor progression and enhance
proinflammatory cytokines to induce a systemic anti-tumor
immune response. In the study by Kang et al., the median
follow-up period was relatively short in the RFA + Stent
and stent alone groups (135 and 119.5 days, respectively)
[12]. And the majority of enrolled participants were diag-
nosed with unresectable pancreaticobiliary malignancy
with metastasis; thus, they had a short life expectancy that
could not be treated with repeated RFA treatment to slow the
growth of the tumor. These factors may obscure the benefit
of RFA in improving survival.
This study also evaluated whether primary tumor sites
can modify the efficacy of RFA + Stent treatment. MBO
includes various tumors such as cholangiocarcinoma, pan-
creatic cancer, gallbladder carcinoma, and ampullary cancer.
5567
The pooled results showed that both subgroups (cholan-
giocarcinoma and all tumors except cholangiocarcinoma)
demonstrated significant benefit of clinical survival in the
RFA + Stent group (Table 3). However, in this study, 59.82%
of these patients were diagnosed with cholangiocarcinoma,
20.4% patients with pancreatic cancer, and the remaining
19.78% patients with other cancers (including gallblad-
der, ampullary, gastric, rectal cancers, and so on). Thus,
we should carefully consider these results that the survival
benefits maybe not be because of the addition of RFA to the
stenting but the difference in disease biology itself.
Current studies on the efficacy of RFA plus additional
nonsurgical anti-tumor therapies for patients with unresect-
able MBO remain controversial. Yang et al. investigated
RFA plus 5-fluorouracil compound (S-1) versus RFA alone
for unresectable extrahepatic cholangiocarcinoma [44].
They suggested that patients with RFA + S-1 were associ-
ated with more prolonged survival and stent patency than
RFA alone [44]. In our study, the pooled results showed
that both subgroups, patients with or without additional non-
surgical anti-tumor therapies, demonstrated significant ben-
efit of clinical survival in the RFA + Stent group compared
with stent alone. However, there were only two eligible
studies in the subgroup of patients without such treatments,
which decreased the quality of the evidence [11, 36]. Such
treatments were very commonly used as a part of pallia-
tive care for patients with unresectable MBO. Thus, future
prospective multicenter studies with more homogeneous
participators are expected to verify the efficacy and safety
of RFA + Stent combined with such nonsurgical anti-tumor
therapies.
Another important advantage provided by RFA + Stent
compared with stent alone is the longer stent patency time.
However, it is noteworthy that the pooled results of included
RCTs reported conflicting results for stent patency, and a
high heterogeneity (I2 = 98%) was found in this subgroup
(Table 2). In the eligible RCTs, Gao et al. [9] and Kang
et al. [12] suggested the median stent patency time during
the follow-up period was not significantly different between
the two interventions (all P > 0.05). After carefully reading
the two articles, we found that patients in the study by Gao
et al. were placed in plastic biliary after RFA [9]. And as
described above, the median follow-up period of the study
by Kang et al. was too short of comparing the long-term
stent patency (more than 3 months) between the two inter-
ventions [12]. Moreover, in the RCTs subgroup, all mean
and standard deviation data for meta-analysis were converted
from the median and their 95% CI, which may also affect the
accuracy of these pooled results.
The biliary stent will frequently become occluded with
the progress of tumors, especially in the plastic stent [6, 7].
Currently, the relevant trials and meta-analyses have proved
the advantage of the metal stent in improving bile duct
13
5568
patency [41, 45]. Our study also showed similar results in
subgroup analysis that RFA combined with uncovered metal
stent seemed to demonstrate better biliary stent patency
(Table 3). Furthermore, this study found no statistical dif-
ference in the short stent patency rate (3 months) and the
degree of alleviation of serum bilirubin and stricture diam-
eter between the RFA + Stent and stent alone groups. But
the RFA + Stent group had a superiority of long-term stent
patency rate (6 months). These results may reflect the effi-
cacy of repeated RFA in destroying local tumors and slow-
ing tumor progress, providing better outcomes for patients
with longer life expectancy.
This study found no significant difference between the
two interventions regarding the incidences of procedure-
related adverse events. Theoretically, there might be poten-
tial thermal injury leading to serious adverse events of adja-
cent vessels and walls of the bile duct during RFA treatment
[9, 16]. Tal et al. reported two patient deaths: one due to
spontaneous hemobilia occurring and the other due to stent
extraction [46]. To date, most of the relevant studies have not
reported thermal injury-related complications such as bile
duct perforation, gastrointestinal perforation, severe bleed-
ing, or liver infarction. Especially in the studies evaluating
the novel temperature-controlled RFA, it could better avoid
unintended hyperthermic damage [12, 13]. The RCT by Gao
et al. also investigated the early and late adverse events, and
they reported similar results that no significant difference
was found between the two interventions [9]. Moreover, they
found the most common of both early and late adverse events
was cholangitis. These patients with cholangitis just need to
receive systemic antibiotic therapy without additional endo-
scopic or percutaneous interventions [9]. According to the
current study, RFA + Stent can be considered a safe pallia-
tive therapy for patients with unresectable MBO.
This study had several limitations. Firstly, this study
included all eligible articles (3 RCTs and 16 observational
studies). Although we reported and discussed these results
based on subgroup analyses of study designs (RCTs or non-
RCTs), the evidence may not be convincing because non-
RCTs mainly drove them. Secondly, subgroup analyses of
overall survival and cholangitis were performed according
to several variables. Still, we should carefully consider these
results due to a few studies with a small sample size in each
subgroup. Lastly, since this study put all tumor types in one
basket, the superior and patency maybe not be because of the
addition of RFA to the stenting but because of the difference
in disease biology itself. Moreover, additional nonsurgical
anti-tumor therapies and stent materials are also main con-
founders, which decrease this evidence's quality although
great efforts have been made to minimize the impact of con-
founders. Better stratified trails with better design are badly
needed to validate the current results and draw more reliable
conclusions.
13
Surgical Endoscopy (2022) 36:5559–5570
Conclusion
In conclusion, in the treatments of unresectable MBO, the
alleviation of serum bilirubin and stricture diameter did not
differ between the RFA + Stent and stent alone groups. How-
ever, RFA + Stent showed superior benefits to stent alone
in terms of the survival and stent patency with comparable
procedure-related adverse events. Given superior efficacy
and comparable complications, RFA + Stent should be rec-
ommended as an attractive alternative to biliary stent alone
for patients with unresectable MBO. However, due to sev-
eral limitations in our study, future prospective multicenter
studies with more homogeneous participators are expected
to verify these results.
Supplementary Information The online version contains supplemen-
tary material available at https://d​ oi.o​ rg/1​ 0.1​ 007/s​ 00464-0​ 22-0​ 9181-2.
Author contributions All patients participated in the interpretation of
study results and approved the final version of the manuscript. TG
and KY contributed to studying concepts and design. SS, HJ, and QC,
contributed to data collection, statistical analysis, data interpretation,
and the paper's drafting. SG, KL, WY, CL, TL, HT, and XL contributed
to data collection.
Funding This research is supported by the Fundamental Research
Funds for the Central Universities (Grant Nos. 2020jbkyzx001, lzu-
jbky-2020-kb20); the Key Laboratory of Evidence-Based Medicine
and Knowledge Translation Foundation of Gansu Province (Grant No.
GSEBMKT-2021KFKT03); Key Laboratory of Molecular Diagnosis
and Precision Therapy of Surgical Tumors of Gansu Province, Grant
Number 2019GSZDSYS06.
Declarations
Disclosures Shaoming Song, Haojie Jin, Qinghao Cheng, Shiyi Gong,
Kun Lv, Wenwen Yang, Caining Lei, Ting Lei, Hongwei Tian, Xiao-
fei Li, Kehu Yang, and Tiankang Guo have no conflicts of interest or
financial ties to disclose.
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