Liver resection versus radiofrequency ablation for hepatitis B virus-related small hepatocellular carcinoma
Journal of Hepatocellular Carcinoma
Liver resection versus radiofrequency ablation for hepatitis B virus-related small hepatocellular carcinoma
Bin Liang 1 2
Siyang Yao 1
Jiapeng Zhou 0
Zongkui Li 1 2
Tianqi Liu 1
0 Department of Hepatobiliary Surgery, The First People's Hospital of Qinzhou , Qinzhou , People's Republic of China
1 Department of Hepatobiliary Surgery, The People's Hospital of Guangxi Zhuang Autonomous Region , Nanning
2 Department of Graduate School, The Guangxi Medical University
frde roF PowerdbyTCPDF(ww.tcpdf.org) recommended. Background: To compare the outcomes of liver resection (LR) with radiofrequency ablation (RFA) for patients with hepatitis B virus (HBV)-related small hepatocellular carcinoma (HCC). Methods: A total of 122 HBV-related small HCC patients who underwent LR (n=64) or RFA (n=58) were involved in this retrospective study. Their basic clinical data, postoperative complications, survival outcomes, and prognostic factors were compared and analyzed. Results: Patients in the LR group had more serious complications (11 versus 0) and longer postoperative hospital stays (11.3 versus 6.0 days) than those in the RFA group (all P<0.05). LR was associated with better recurrence-free survival (RFS) rates at 1, 3, and 5 years compared with RFA (90.4%, 65.9%, and 49.5% versus 79.3%, 50.3%, and 35.6%, P=0.037), but there was no significant difference in overall survival (OS) (95.2%, 78.1%, 58.6% versus 93.1%, 71.3%, 52.9%, P=0.309). Multivariate Cox analysis showed that the hepatic cirrhosis (hazard ratio [HR]: 2.13), tumor number (HR: 3.73), tumor diameter (HR: 1.92), and postoperative anti-HBV therapy (HR: 0.53) had predictive values for RFS, and the latter three (HR: 4.34, 2.30, and 0.44) were independent predictors of OS (all P<0.05). Conclusion: LR might be considered the preferred method for patients with HBV-related small HCC, while RFA could apply to selective cases. Anti-HBV therapy after treatment was Hepatocellular carcinoma (HCC) is one of the most prevalent primary malignancies of the liver and is the leading cause of cancer-related deaths.1 The high incidence is partly due to the elevated chronic hepatitis B virus (HBV) prevalence, which is seen in 55%-60% of persons worldwide and in more than 70% in Asian countries in patients with HCC.2 Currently, liver resection (LR) and radiofrequency ablation (RFA) are usually considered as curative treatments of small HCCs, while the donor shortage greatly limits the applicability of liver transplantation.3 Over the past decades, although many studies worldwide have investigated the treatment of LR and RFA in patients with small HCCs, the use of these methodologies remains a controversial issue and has not yet been standardized, especially in the East, with its high prevalence of HBV infection.4 In this study, we compared the outcomes and explored the relevant prognostic factors of patients with HBV-related
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small HCC who underwent LR or RFA as the primary treatment through retrospective
analysis, aiming to determine the efficacy of different
This study was approved by the People’s Hospital of Guangxi
Zhuang Autonomous Region Institutional Review Board
and conformed to the ethical guidelines of the Declaration
of Helsinki. A total of 578 patients with HCC underwent
LR or RFA as the primary treatment from January 2011 to
December 2016 in our hospital. Their medical records were
retrospectively reviewed. Of these, 122 patients were selected
in this study who met the following criteria: 1) the presence
of small HCC (≤5 cm or ≤3 cm and no more than 3 lesions);
2) comorbid chronic HBV infection; 3) Child–Pugh class A
or B and good performance status; 4) absence of vascular
invasion, decompensated liver cirrhosis, and metastatic
The diagnosis of HCC was confirmed by histopathology after
resection for patients in the LR group, while percutaneous
needle biopsy was performed for all of the patients in the RFA
group. Primary treatment was defined before any previous
treatment in both groups at the time of diagnosis of HCC.
HBV-related HCC was identified in the patients with HCC
who were diagnosed with coexisting presence of serum
hepatitis B surface antigen.5 Contrast-enhanced ultrasound and/or
multiphase contrast-enhanced spiral computed tomography
scan with an instrumental criterion was used in the diagnosis
of cirrhosis and in the measurement of the tumor number
and diameter. Recurrence was defined as the emergence of
a new tumor inside or outside the liver, including residual
active tumor within or near the previous site found more than
1 month following the first treatment.
The therapeutic benefits and potential risks of LR and RFA were
provided to each patient in detail, and the final treatment
modality was determined by individual patients after the surgeon’s
suggestion was given. Informed consent forms were signed by
all of the included patients before the treatment of LR or RFA.
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Both LR and RFA were performed by the same
experienced surgical group. Anatomical liver resection (ALR) was
given priority to be applied to the patients while it was
possible, and nonanatomical liver resection (NALR) was used in
tumors adjacent to the main vasculature, and attempts were
made to maintain an adequate surgical margin of at least 1.0
cm. Percutaneous RFA was conducted under sonographic
(SSD-3500, Aloka, Chiba, Japan) guidance operated by the
same experienced sonographer, and the tumors were
completely ablated in automatic impedance control mode with
the Radiofrequency System (RF 2000, USA). Percutaneous
ethanol injection (PEI) was combined with RFA when the
HCC lesions were in high-risk locations, such as near major
vasculature, the liver surface, the gallbladder, or the
All of the patients selected in the study were followed up
with biochemical liver function and serum alpha-fetoprotein
(AFP) tests and ultrasonography or computed tomography/
magnetic resonance imaging examinations every 3–6 months
until death or the end of the study. Recurrent tumors were
managed by individualized therapy plans, which included
repeated LR or RFA, transcatheter arterial
chemoembolization, and oral sorafenib therapy. The time to tumor recurrence
and overall survival (OS) were recorded. Follow-up data were
collected until December 31, 2016.
The data of the patients were statistically analyzed using
IBM SPSS software, version 22.0 (Armonk, NY, USA)
for Windows. Continuous variables were evaluated with a
single-factor analysis of variance. Categorical variables were
compared using the chi-square test. Recurrence-free survival
(RFS) and OS data were analyzed using the Kaplan–Meier
method, and all survival curves in the two groups were
compared using the log-rank test. Moreover, a Cox regression
model was used to identify the prognostic factors.
Multivariate analysis was executed for those factors with P-values<0.2
in univariate analysis. A P-value<0.05 was considered to
indicate a statistically significant difference.
In this study, 122 patients who satisfied the inclusion criteria
were selected: 64 of these underwent LR and 58 were treated
with RFA. In the LR group, 47 patients received ALR, and
17 underwent NALR. In the other group, 37 patients were
treated with RFA alone, and the remaining 21 had combined
therapy with PEI. All of them were diagnosed with HCC by
histopathology after treatment. The median follow-up times
were 34.9 months (range, 7–66 months) in the LR group and
36.1 months (range, 9–66 months) in the RFA group.
The baseline characteristics of all of the patients in both
the LR and RFA groups are shown in Table 1. All the data
of sex, age, serum carcinoembryonic antigen (CEA), the
positive rate of AFP, total bilirubin (TB), albumin (ALB),
alanine aminotransferase (ALT), and aspartate
aminotransferase (AST), platelet count (PLT), the hepatitis B virus DNA
levels (HNB-DNA), Child–Pugh classification, the presence
of cirrhosis, the tumor number, and the maximum tumor
diameter in both groups showed no significant differences
between the two groups (all P>0.05). In addition, the number
of patients who received anti-HBV therapy after surgery was
34 (53.1%) in the LR group and 37 (63.8%) in the RFA group
Postoperative characteristics are presented in Table 2. Patients
in the LR group tended to have lower ALB and higher ALT
and AST than those in the RFA group (all P<0.001), and
they were also more vulnerable to having procedure-related
complications (11 versus 0, P=0.001), including hydrothorax
(1 case), ascites (2 cases), elevated serum pancreatic α-amylase
(6 cases), bleeding (1 case), and subphrenic infection (1 case).
Furthermore, patients who received resection experienced
longer postoperative hospital stays than those who underwent
ablation; the median postoperative hospital days were 11.3 days
(range, 7–25 days) in the LR group and 6.0 days in the RFA
group (range, 3–10 days) (P<0.001). However, postoperative
TB, 7-days AFP >400 ng/mL, and temperature ≥38.5°C were
not significantly different between the two groups. There were
no perioperative deaths in either group.
Recurrence and survival
At the time of censoring, recurrence was observed in 23 of 64
(35.9%) patients in the LR group and 32 of 58 (55.2%) in the
RFA group (P=0.033). The cumulative RFS rates at 1, 3, and
5 years were estimated to be 90.4%, 65.9%, and 49.5% in the
LR group and 79.3%, 50.3%, and 35.6% in the RFA group,
respectively (Figure1A). The RFS rates were significantly
higher in the LR group (P=0.037). There were 14 (21.9%)
patients who died in the LR group and 19 (32.8%) in the RFA
group (P=0.177). The 1-, 3-, 5-year cumulative OS rates in
the LR group were 95.2%, 78.1%, and 58.6% and those in
the RFA group were 93.1%, 71.3%, and 52.9%, respectively
(Figure1B). There were no significant differences between
the two groups in OS (P=0.309).
Prognostic factors for outcomes
In univariate analysis of RFS, the P-values for CEA, AST,
PLT, hepatic cirrhosis, number of tumors, maximum tumor
diameter, and postoperative anti-HBV therapy were all <0.20.
The multivariate analysis of these seven variables showed that
hepatic cirrhosis (hazard ratio [HR]: 2.13, 95% CI: 1.13–2.76,
P=0.019), number of tumors (HR: 3.73, 95% CI: 1.93–7.20,
P<0.001), maximum tumor diameter (HR: 1.92, 95% CI:
1.34–2.76, P<0.001), and postoperative anti-HBV therapy
(HR: 0.49, 95% CI: 0.30–0.91, P=0.022) were independent
prognostic factors associated with RFS.
For OS, univariate analysis showed that the P-values
of AST, number of tumors, maximum tumor diameter, and
postoperative anti-HBV therapy were all <0.20. However, by
multivariate analysis, the number of tumors (HR: 4.34, 95%
CI: 1.98–9.52, P<0.001), maximum tumor diameter (HR:
2.30, 95% CI: 1.44–3.69, P=0.001), and postoperative
antiHBV therapy (HR: 0.44, 95% CI: 0.22–0.89, P=0.023) were
significant, independent predictors of OS. Further details are
presented in Tables 3 and 4.
HBV infection is one of the most prevalent risk factors in
the development of HCC worldwide, and a large body of
research has confirmed the association between viral
infection and the occurrence of HCC.7,8 Although routine HCC
surveillance of HBV-infected subjects could improve their
survival, it has been reported that HBV-related HCC patients
have significantly poorer outcomes after treatment than
those without HBV infection.9,10 In past decades, numerous
studies have compared the outcomes of patients with HCC
who underwent LR or RFA; however, there has not been a
consistent opinion on which treatment method is superior.
Some researchers have confirmed that patients who receive
LR have a significantly higher survival rate than those who
receive RFA,11–15 while some investigations have indicated
similar long-term outcomes between the two treatments,16–19
and have even reported that RFA was associated with better
treatment efficacy than LR in patients with small HCC.20
Currently, among HBV-related small HCC cases, there are no
Recurrence-free survival curve
Overall survival curve P=0.037 P=0.309
HR (95% CI)
data comparing the clinical outcomes of LR with RFA, and
our study was performed to explore the difference between
these two treatments in such a cohort.
Recently, several studies have reported that LR was
associated with a lower recurrence risk but similar OS, compared
with RFA in early-stage HCC patients.14,21,22 Consistent
with this finding, our study also found the same outcomes
between LR and RFA in HBV-related small HCC. Patients
in the LR group achieved better cumulative RFS rates at 1,
3, and 5 years than those in the RFA group (P=0.037) but
comparable OS rates between the two groups (P=0.309).
LR has the advantage of removing the tumor-adjacent
territory, likely including minute satellite lesions, especially in
patients who underwent anatomical resection, which could
offer better local control of HCC than RFA.23 In the present
study, recurrence was observed in 55.2% (32/50) of cases in
the RFA group, which was significantly higher than in the LR
group with 35.9% (23/64) relapse during the follow-up period
(P=0.033). According to previous reports, the recurrence rate
in HBV-related HCC patients who underwent RFA treatment
was 52.4%–60.8% after a 5-year follow-up, and the risk of
recurrence was increased with the lower PLT, higher HBV
DNA levels, and the tumor topographical factors (including
the number, larger size, and proximity to major vessels or
Despite a significantly lower RFS in the RFA group, the
OS was comparable in both groups. Such outcomes could
probably be attributed to regular visits after surgery, which
could detect early recurrence and ensure that patients received
timely retreatment with individual methods.21 Additionally,
our study showed that patients who underwent RFA
experienced fewer treatment-related complications and shorter
postoperative hospital stays. These results were consistent
with previous studies.11–14,16 Accompanied by the advantage
18 of liver functional reserve, offering better tolerability, good
l-20 repeatability, and cost-effectiveness,29 RFA could be
consid-J3u ered an alternative therapy for selected patients with small
1no HCC, such as those with worse liver function and older
.631 In these patients, the results of multivariate analysis in our
..731 study showed that the presence of hepatic cirrhosis, multiple
y54 tumors, and larger tumor diameter were significant
indepen/b dent risk predictors of RFS, while only multiple tumors and
.com larger tumor diameter were risk factors associated with OS.
rse Similarly, a previous study demonstrated that intervention
pe (resection versus ablation), tumor number, tumor diameter,
.vdow l.yno and a high level of serum AFP were independent risk factors
/ww sue for RFS and OS for early-stage HCC.13 This finding
sug:/tsp lna gests that HBV-related HCC patients with hepatic cirrhosis,
tohm rspeo multiple tumors, and larger tumor diameters should undergo
frde roF enhance surveillance after treatment, especially those who
ad undergo RFA.
lnw Our study showed that postoperative anti-HBV therapy
ado was an independent protective factor for both RFS and
nom OS. This result was in agreement with several previous
irca studies.30–33 A randomized controlled trial demonstrated
lllrueaC trhecautrarnetni-cHeBaVndt himerparpoyveadfteOr StreinatmpaetnietnstisgnwiiftihcaHntBlyVr-eredluacteedd
tcao HCC.30 Urata et al31 suggested that a high serum level of HBV
peH DNA was a notable risk factor for recurrence after surgery for
lfoa HBV-related HCC, and antiviral therapy could improve the
runo long-term outcomes. Ke et al32 indicated that postoperative
J anti-HBV therapy could significantly prolong survival time
by increasing the likelihood of the patient receiving
curative treatments in the event of a relapse and that it prevented
death due to liver failure, especially in patients with early- or
median-stage HCC. Hence, anti-HBV therapy after LR or
RFA can be highly recommended in patients with
HBVrelated small HCC to attain the benefit of better outcomes.
There were several limitations in our study. First, because
of the retrospective study design, there was potential for
selection bias, as well as with the presence of uncontrolled
confounding factors between the two groups. Second, there is
no comparison of recurrence patterns and treatment
modalities for recurrent tumor which may influence the results in this
study. However, we plan to further our study by increasing
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the sample size and comparing the recurrence to confirm the
outcomes of these cohorts after treatment.
For patients with HBV-related small HCC, LR provided better
RFS than RFA but had a similar OS in comparison. Patients
who underwent RFA had fewer complications and shorter
postoperative hospital stays. LR might be considered the
preferred method for these patients, while RFA could apply
to selective patients who would be unable to tolerate surgical
resection. Hepatic cirrhosis, tumor number, and maximum
tumor diameter were independent prognostic factors of
longterm outcomes in this cohort, and anti-HBV therapy after
treatment was recommended.
This study was supported by grants from the Project of
Guangxi Scientific Research and Technology Development
plan, China (2013BC26214). The authors thank Dr Xixia Liu
and Dr Xiaofeng Dong, who have been a source of
encouragement and inspiration.
The authors report no conflicts of interest in this work.
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