Canadian Journal of Gastroenterology and Hepatology
Volume 2018 (2018), Article ID 1746895, 15 pages
https://doi.org/10.1155/2018/1746895

Review Article

Laparoscopic versus Open Surgery for Hepatocellular Carcinoma: A Meta-Analysis of High-Quality Case-Matched Studies

Ke Chen,¹ Yu Pan,¹ Bin Zhang,¹ Xiao-long Liu,¹ Hendi Maher,² and Xue-yong Zheng¹

¹Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, 3 East Qingchun Road, Hangzhou, Zhejiang 310016, China
²School of Medicine, Zhejiang University, 866 Yuhangtang Road, Hangzhou, Zhejiang 310058, China

Correspondence should be addressed to Xue-yong Zheng; 3306053@zju.edu.cn

Received 5 November 2017; Revised 5 December 2017; Accepted 23 January 2018; Published 1 March 2018

Academic Editor: Kevork M. Peltekian

Copyright © 2018 Ke Chen et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract.

Objective. To present a meta-analysis of high-quality case-matched studies comparing laparoscopic (LH) and open hepatectomy (OH) for hepatocellular carcinoma (HCC). Methods. Studies published up to September 2017 comparing LH and OH for HCC were identified. Selection of high-quality, nonrandomized comparative studies (NRCTs) with case-matched design was based on a validated tool (Methodological Index for Nonrandomized Studies) since no randomized controlled trials (RCTs) were published. Morbidity, mortality, operation time, blood loss, hospital stay, margin distance, recurrence, and survival outcomes were compared. Subgroup analyses were carried out according to the surgical extension (minor or major hepatectomy). Results. Twenty studies with a total of 830 patients (388 in LH and 442 in OH) were identified. For short-term surgical outcomes, LH showed less morbidity (RR = 0.55; 95% CI, 0.47~0.65; ), less mortality (RR = 0.43; 95% CI, 0.18~1.00; ), less blood loss (WMD = −93.21 ml, 95% CI, −157.33−29.09 ml; ), shorter hospital stay (WMD = −2.86, 95% CI, −3.63−2.08; ), and comparable operation time (WMD = 9.15 min; 95% CI: −7.61~25.90, ). As to oncological outcomes, 5-year overall survival rate was slightly better in LH than OH (HR = 0.66, 95% CI: 0.52~0.84, ), whereas the 5-year disease-free survival rate was comparable between two groups (HR = 0.88, 95% CI: 0.74~1.06, ). Conclusion. This meta-analysis has highlighted that LH can be safely performed in selective patients and improves surgical outcomes as compared to OH. Given the limitations of study design, especially the limited cases of major hepatectomy, methodologically high-quality comparative studies are needed for further evaluation.

1. Introduction

Although the incidence of hepatocellular carcinoma (HCC) has decreased, HCC is still the fifth most common malignancy and the third leading cause of cancer-related death worldwide [1]. Since laparoscopic hepatectomy (LH) was first reported in 1996 [2, 3], this treatment has been considered a landmark development in the progress of surgical treatment. However, the majority of HCC patients usually have cirrhosis and hypohepatia. Because of this, hepatectomy increases the risk of developing significant postoperative complications including ascites, hepatic failure, encephalopathy, and portal vein thrombosis [4]. There are some controversial aspects of LH for HCC including complications, postoperative recovery, and long-term survival outcomes.

During the last 6 years, a number of meta-analyses that compare LH with open hepatectomy (OH) for HCC have been published [5–8]. Although randomized controlled trials (RCTs) are the most ideal tools for meta-analysis, no RCTs on this topic have been yet conducted. These meta-analyses included the available nonrandomized comparative studies (NRCTs) to overcome the paucity of RCTs. Therefore unreliable results and little strong evidence had been presented. On the other hand, there was evidence that estimates derived from high-quality NRCTs may be similar to those derived from RCTs [9]. Also, when comparing surgical procedures, pooling of high-quality NRCTs could be as accurate as pooling of RCTs [10]. In addition, several comparative studies on this topic have been published in the last 3 years and none of the published meta-analyses included studies published after 2013. Therefore, we performed an updated meta-analysis evaluating all of the available high-quality published trials to compare LH with OH for HCC.

2. Methods

2.1. Systematic Literature Search

Systematic searches of PubMed, Embase, Cochrane Library, and Web of Science were performed to identify articles published up to September 2017. Searches included the terms “laparoscopic,” “minimally invasive,” “hepatectomy,” “liver resection,” “hepatocellular carcinoma,” and “HCC”. All eligible studies in English were retrieved, and their bibliographies were checked for potential relevant publications.

2.2. Eligibility Criteria and Quality Assessment

In order to reduce bias, our meta-analysis synthesized the existing observational studies while strictly limiting inclusion and exclusion criteria. First of all, papers containing any of the following were excluded: (1) studies that included malignant lesions other than HCC, (2) studies focusing on recurrent HCC, (3) studies that included cases of robotic-assisted hepatectomy. Secondly, only studies designed with case-matched analysis were further evaluated and nonmatched studies were excluded. Then, the methodological quality of the eligible nonrandomized comparative studies (NRCTs) was assessed by the Methodological Index for Nonrandomized Studies (MINORS) [11]. In total, 8 items were evaluated, with a maximum score of 16 points. Studies with 12 or more points were considered of high quality and were included in the meta-analysis. Those with less than 12 points were excluded. Besides, if there was overlap between authors or centers, only the higher-quality or more recent literature was selected.

2.3. Data Extraction and Quality Assessment

Two researchers evaluated all the titles and abstracts. Then they assessed the selected full-text articles for eligibility. This work was then reevaluated and confirmed by a senior researcher. The measured outcomes of all eligible publications can be divided into two categories: ① short-term outcomes (operation time, estimated blood loss, transfusion, length of hospital stay, morbidity, and mortality); ② oncological outcomes (tumor size, margin distance, R0 resection, recurrence, and survival). The postoperative morbidity was cataloged according to the Clavien-Dindo classification. Minor complication refers to Grade I and Grade II complications, and major complication includes Grade III to V complications.

2.4. Subgroup Analysis

Because the different levels of hepatectomy can lead to different outcomes, and major hepatectomy is a technically dependent and time-consuming procedure, subgroup analyses were carried out according to surgical extensions. Included studies were assigned to 3 subgroups: minor hepatectomy, mixed hepatectomy, and major hepatectomy.

2.5. Statistical Analysis

The risk ratio (RR) was utilized to analyze the dichotomous variables, and the weighted mean difference (WMD) was utilized to assess the continuous variables. If the study provided medians and ranges instead of means and standard deviations (SDs), we estimated the means and SDs as described by Hozo et al. [12]. Heterogeneity was evaluated by Cochran’s statistic and Higgins statistic [13]. If data was not significantly heterogeneous ( or < 50%), the pooled effects were calculated using a fixed model. Otherwise, the pooled effects were calculated using a random model. The hazard ratios (HRs) of a 5-year overall survival rate (OS) and a 5-year disease-free survival rate (DFS) were used with a generic inverse variance meta-analysis. The log HR and its SE were estimated using the method introduced by Tierney et al. [14]. According to the overall morbidity, potential publication bias was determined by carrying out an informal visual inspection of funnel plots. A two-tailed value of was considered significant. All statistical tests were performed with Review Manager version 5.1 (The Cochrane Collaboration, Oxford, England).

3. Results

3.1. Search Results and Baseline Characteristics

The last search was performed on September 20, 2017. A total of 968 potential published articles were initially identified from the search. Of these, 63 articles were selected based on their titles and abstracts, and a full examination of the texts was performed. Further 37 papers were excluded, after being read thoroughly, due to (1) including non-HCC cases (), (2) focusing on recurrent HCC (), (3) robot-assisted hepatectomy (), (4) overlap patient cohorts (), or (5) nonmatched comparative studies (). Then 26 studies were selected for quality assessment, and 6 studies were excluded by a modified MINORS score < 12 [15–20]. Finally, 20 studies were selected for final meta-analysis [21–40]. A flow chart of the search strategies, which contains reasons for excluding studies, is elucidated in Figure 1. The details of the selection process, which included the references of excluded studies and the MINORS assessments of low-quality studies, could be found in Supplementary Materials (available here).

Figure 1: Flow chart of literature search strategies.

3.2. Study Characteristics

A total of 830 patients were included in the analysis with 388 undergoing LH (46.8%) and 442 undergoing OH (53.2%). The characteristics of these included studies are summarized in Table 1. Studies were well matched in terms of age, gender, ASA classification, body mass index (BMI), tumor size, and surgical extension. Eight studies reported only minor hepatectomy, and three studies focused on major hepatectomy, whereas the remaining nine studies included both minor and major hepatectomy. The majority of studies graded morbidity according to the Clavien-Dindo classification, with the study by Lee et al. being the only exception [24]. The assessments of the NRCTs are illustrated in Table 2. Each trial received more than 12 points (the maximum possible score is 16) and was considered to be of the highest quality (see Supplementary Materials).

Table 1: Basic information of the included literature.

Author
Region
Year
Study period
Sample size
Matching method
Cirrhosis (%)
Surgical extension
Conversion (%)
Clavien-Dindo

LH
OH
LH
OH

Belli et al.
Italy
2007
2000–2004
23
23
CCM
100
100
Minor
4.3
Yes

Tranchart et al.
France
2010
1999–2008
42
42
CCM
73.8
81
Mixed
4.8
Yes

Kim et al.
Korea
2011
2005–2009
26
29
CCM
92.3
86.2
Mixed
E
Yes

Truant et al.
France
2011
2002–2009
36
53
CCM
100
100
Minor
19.4
Yes

Lee et al.
Hong Kong
2011
2004–2010
33
50
CCM
84.8
64
Minor
18.2
NA

Ahn et al.
Korea
2014
2005–2013
51
51
PSM
68.6
66.8
Mixed
9.8
Yes

Kim et al.
Korea
2014
2000–2012
29
29
PSM
62.1
65.5
Minor
E
Yes

Memeo et al.
France
2014
1990–2009
45
45
CCM
100
100
Minor
NA
Yes

Lau et al.
USA
2015
2008–2014
26
26
CCM
80.8
73.1
Mixed
35
Yes

Lee et al.
Canada
2015
2006–2013
43
86
CCM
NA
NA
Mixed
14
Yes

Luo et al.
China
2015
2008–2015
53
53
CCM
100
100
Minor
E
Yes

Takahara et al.
Japan
2015
2000–2010
387
387
PSM
61.7
59.6
Mixed
6.5
Yes

Han et al.
Korea
2015
2004–2013
88
88
PSM
62.5
59.1
Mixed
9.1
Yes

Yoon et al.
Korea
2015
2007–2011
58
174
PSM
NA
NA
Mixed
0
Yes

Cheung et al.
Hong Kong
2016
2002–2015
110
330
PSM
100
100
Mixed
5.5
Yes

Sposito et al.
Italy
2016
2006–2013
43
43
PSM
100
100
Minor
4.7
Yes

Jiang et al.
China
2016
2008–2013
59
59
PSM
100
100
Minor
5.1
Yes

Komatsu et al.
France
2016
2000–2014
38
38
CCM
NA
NA
Major
31.6
Yes

Yoon et al.
Korea
2017
2008–2015
33
33
PSM
100
100
Major
NA
Yes

Xu et al.
China
2017
2015–2017
32
32
PSM
100
100
Major
NA
Yes

CCM: case by case matching; PSM: propensity score matching; E: conversion cases were excluded from the studies; NA: not available.

Table 2: Modified MINORS score of all eligible nonrandomized comparative studies.

Author
①
②
③
④
⑤
⑥
⑦
⑧
Score

Belli et al.
2
2
1
2
2
1
2
1
13

Tranchart et al.
2
2
1
1
2
1
2
2
13

Kim et al.
2
1
1
2
2
2
1
1
12

Truant et al.
2
2
1
1
2
2
1
1
12

Lee et al.
2
2
1
1
2
2
1
1
12

Ahn et al.
2
2
1
1
2
2
2
2
14

Kim et al.
2
1
1
2
2
2
1
1
12

Memeo et al.
2
1
1
1
2
1
2
2
12

Lau et al.
2
1
2
1
2
2
2
1
13

Lee et al.
2
1
1
1
2
2
1
2
12

Luo et al.
2
1
1
1
2
2
2
2
13

Takahara et al.
2
1
1
1
2
2
2
2
13

Han et al.
2
1
1
1
2
2
2
2
13

Yoon et al.
2
1
1
1
2
2
1
2
12

Cheung et al.
2
2
1
1
2
2
2
2
14

Sposito et al.
2
2
1
1
2
2
2
2
14

Jiang et al.
2
1
1
1
2
2
2
2
13

Komatsu et al.
2
1
1
1
2
2
2
1
12

Yoon et al.
2
1
2
2
2
2
2
1
14

Xu et al.
2
2
2
1
2
2
2
1
14

① Consecutive patients, ② prospective data collection, ③ reported endpoints, ④ unbiased outcome evaluation, ⑤ appropriate controls, ⑥ contemporary groups, ⑦ groups equivalent, ⑧ sample size.

3.3. Meta-Analysis of Short-Term Outcomes

3.3.1. Operation Time

Operative time was reported in all studies [21–40]. Statistically significant between-study heterogeneity was identified in all subgroups (, = 87.2%). There was no significant difference between the groups’ operation times (Table 3). However, in the subgroup of major hepatectomy, the overall effect size of the mean operation time was significantly longer in LH than that in OH (WMD = 77.93 min, 95% CI: 40.45~115.41, ).

Table 3: Overall outcomes of the meta-analysis.

Outcomes
Studies No.
Sample size
Heterogeneity
(, )
Model
Overall effect size
95% CI of overall effect

LH
OH

Operation time (min)
20
1255
1671
<0.01, 87%
R

0.28

    Minor hepatectomy
8
321
355
<0.01, 78%
R

0.17

    Mixed hepatectomy
9
831
1213
<0.01, 83%
R

0.29

    Major hepatectomy
3
103
103
0.05, 67%
R

<0.01

Blood loss (mL)
17
1128
1425
<0.01, 92%
R

−157.33~−29.09
<0.01

    Minor hepatectomy
7
278
312
0.39, 5%
R

−98.41~−54.01
<0.01

    Mixed hepatectomy
7
747
1010
0.05, 52%
R

−294.57~−131.31
<0.01

    Major hepatectomy
3
103
103
0.88, 0%
R

0.88

Transfusion
14
979
1352
0.90, 0%
F

0.03

    Minor hepatectomy
4
121
155
0.49, 0%
F

0.22

    Mixed hepatectomy
8
788
1127
0.86, 0%
F

0.06

    Major hepatectomy
2
70
70
0.28, 15%
F

0.70

Hospital stay (days)
20
1255
1671
<0.01, 80%
R

−3.63~−2.08
<0.01

    Minor hepatectomy
8
321
355
<0.01, 76%
R

−4.23~−1.63
<0.01

    Mixed hepatectomy
9
831
1213
0.01, 58%
R

−3.95~−1.76
<0.01

    Major hepatectomy
3
103
103
0.15, 47%
R

−4.60~−0.92
<0.01

Morbidity
20
1255
1671
0.28, 14%
F

<0.01

    Minor hepatectomy
8
321
355
0.29, 17%
F

<0.01

    Mixed hepatectomy
9
831
1213
0.26, 21%
F

<0.01

    Major hepatectomy
3
103
103
0.21, 37%
F

<0.01

Severe complications
18
1196
1476
0.88, 0%
F

<0.01

    Minor hepatectomy
7
288
305
0.96, 0%
F

0.04

    Mixed hepatectomy
8
805
1068
0.44, 0%
F

<0.01

    Major hepatectomy
3
103
103
0.35, 6%
F

0.05

Mortality
9
789
1026
0.88, 0
F

0.05

    Minor hepatectomy
3
104
121
0.34, 7
F

0.21

    Mixed hepatectomy
5
653
873
0.84, 0
F

0.18

    Major hepatectomy
1
32
32
Not applicable
F

0.50

Tumor size (cm)
19
1229
1645
<0.01, 57%
R

0.09

    Minor hepatectomy
8
321
355
0.76, 0%
R

0.48

    Mixed hepatectomy
8
805
1187
0.50, 0%
R

0.28

    Major hepatectomy
3
103
103
<0.01, 92%
R

0.13

Margin distance (cm)
11
501
694
0.14, 47%
R

<0.01

    Minor hepatectomy
5
186
220
0.06, 56%
R

0.03

    Mixed hepatectomy
5
282
441
0.15, 41%
R

0.02

    Major hepatectomy
1
33
33
Not applicable
R

0.18

R0 resection
14
1010
1409
0.70, 0%
F

0.37

    Minor hepatectomy
6
240
257
0.80, 0%
F

0.23

    Mixed hepatectomy
7
738
1120
0.47, 0%
F

0.13

    Major hepatectomy
1
32
32
Not applicable
F

0.56

WMD: weighted mean difference; RR: risk ratio; F: fixed; R: random.

3.3.2. Intraoperative Blood Loss

Blood loss was available from 17 studies [21, 22, 24–34, 36, 37, 39, 40]. Statistically significant between-study heterogeneity was identified in all subgroups (, = 88.1%). The pooled results showed that LH was associated with less blood loss than OH (Table 3). However, in the subgroup of major hepatectomy, there was no significant difference between groups (WMD = 3.75 ml, 95% CI: −60.16~67.65, ).

3.3.3. Blood Transfusion

Fourteen studies recorded perioperative blood transfusion [21–27, 29, 30, 33–35, 37, 39]. There was no evidence of heterogeneity between subgroups (, = 0%). Although none of the subgroups reached a significant difference, the overall pooled data indicated that transfusion rates were lower in LH (RR = 0.73, 95% CI: 0.55~0.96,  ) (Table 3).

3.3.4. Duration of Hospital Stay

The length of hospital stays was pooled for all studies [21–40]. Although statistically significant between-study heterogeneity was identified in each subgroup, there was no evidence of heterogeneity between subgroups (, = 0%). Hospital stays in LH group were shorter than those in OH group (WMD = −2.86 d, 95% CI: −3.63~−2.08, ) (Table 3).

3.3.5. Morbidity

All studies reported their overall complication rates [21–40]. Because there was no statistical evidence of heterogeneity, the effect sizes of all subgroups were synthesized to generate the overall effect size (, = 0%) (Table 3) (Figure 2). The postoperative morbidity rates were 14.0% (176/1255) in LH and 24.2% (404/1671) in OH. In addition the pooled data showed that LH significantly reduced postoperative complications (RR = 0.55; 95% CI, 0.47~0.65; ) (Table 3). Moreover, each subgroup also revealed reduced overall morbidity in the LH group (Table 3).

Figure 2: Forest plot of overall morbidity.

Eighteen studies recorded severe complications [21, 22, 25–40]. Similar to overall morbidity, the results showed that patients in the LH group suffered less severe complications (Table 3). We identified specified complications of ascites, liver failure, and the respiratory system. The results implied that postoperative ascites in patients, regardless of whether they underwent minor or major hepatectomy, was less in LH than in OH (RR = 0.42; 95% CI, 0.31~0.59; ) (Figure 3(a)). Studies that recorded postoperative liver failure reported a lower incidence of liver failure in LH than in OH with one exception by Xu et al. [39]. The overall pooled data revealed that patients in the LH group were less likely to suffer liver failure than those in the OH group (RR = 0.41; 95% CI, 0.27~0.64; ) (Figure 3(b)). LH was also associated with a significant reduction in respiratory complications regardless of different surgical extension (RR = 0.43, 95% CI: 0.28~0.64, ) (Figure 3(c)).

(a)

(b)

(c)

Figure 3: Forest plot of specific complications: (a) ascites, (b) liver failure, (c) respiratory complications.

3.3.6. Mortality

Nine studies recorded cases of postoperative death [21, 22, 25, 28–30, 33, 35, 39]. There was no evidence of heterogeneity between subgroups (, = 0%). These studies showed very low incidences of mortality. However, the overall pooled data indicated a more reduced postoperative mortality in LH than that in OH (RR = 0.43; 95% CI, 0.18~1.00; ) (Table 3).

3.4. Meta-Analysis of Oncological Outcomes

3.4.1. Tumor Size

Only one study did not report tumor size [30]. There was trifling heterogeneity between subgroups, mainly due to the major hepatectomy subgroup (, = 4.2%) (Table 3). Meta-analysis showed that the tumor size of OH was longer than that of LH with a marginal difference (WMD = −0.19 cm; 95% CI: −0.41~−0.03, ), which was mainly due to smaller tumors in LH than those in OH in the major hepatectomy subgroup (Table 3).

3.4.2. Margin Distance

Only 11 studies mentioned the distance of the tumor margin [22, 24–29, 31, 34, 38, 40]. Although statistical significant between-study heterogeneity was identified in each subgroup, there was no evidence of heterogeneity between subgroups (, = 0%). On pooling the results, the margin distance was longer in the LH group than that in the OH group (WMD = 2.61 cm; 95% CI: 1.06~4.17, ) (Table 3).

3.4.3. R0 Resection

The R0 resection was reported in 14 studies [21, 23, 24, 27, 29–36, 38, 39]. There was no obvious heterogeneity (, = 41.8%). The pooled estimate for margin distance indicated comparative outcomes between groups (RR = 1.01, 95% CI: 0.99~1.02, ) (Table 3).

3.4.4. Overall Survival Rate and Disease-Free Survival Rate

Summary of follow-up time, recurrence, and long-term survival rates is listed in Table 4. Nineteen studies reported the detailed long-term outcomes. Among them, the data for 5-year OS rates can be extracted from nine studies and the data for 5-year DFS rates can be extracted from ten studies. The follow-up periods in six studies were less than five years. The survival data of three studies cannot be extracted due to a technical problem with figures. Unfortunately, none of the three major hepatectomy studies can be included in our survival analysis [37, 39, 40]. In all, the pooled 5-year OS rate was slightly better in LH than in OH (HR = 0.66, 95% CI: 0.52~0.84, ) (Figure 4(a)). The 5-year DFS rate was comparable between groups (HR = 0.88, 95% CI: 0.74~1.06, ) (Figure 4(b)).

Table 4: Summary of recurrence and long-term survival.

Author
Group
Follow-up
R
Survival (time: month; rate: %)

Tranchart et al.
LH
29.7
10
1, 3, 5 y-DFS: 81.6, 60.9, 45.6; 1, 3, 5 y-OS: 93.1, 74.4, 59.5.

OH
24.6
12
1, 3, 5 y-DFS: 70.2, 54.3, 37.2; 1, 3, 5 y-OS: 81.8, 73, 47.4.

Kim et al.
LH
21.8
7
MDFS: 13.4; 1 y-DFS: 84.6.

OH
24.8
10
MDFS: 14.6; 1 y-DFS: 82.8.

Truant et al.
LH
35.7
16
5 y-DFS: 35.5; 5 y-OS: 70.

OH
23
5 y-DFS: 33.6; 5 y-OS: 46.

Lee et al.
LH
35.4
15
1, 3, 5 y-DFS: 78.8, 51, 45.3; 1, 3, 5 y-OS: 86.9, 81.8, 76.0.

OH
28.5
19
1, 3, 5 y-DFS: 69.2, 55.9, 55.9; 1, 3, 5 y-OS: 98, 80.6, 76.1.

Ahn et al.
LH
38.6
12
5 y-DFS: 67.8; 5 y-OS: 80.1.

OH
52.3
21
5 y-DFS: 54.8; 5 y-OS: 85.7.

Kim et al.
LH
47.9
11
MDFS: 15.4; MOS: 47.9; 1, 3, 5 y-DFS: 81.1, 61.7, 54.0; 1, 3, 5 y-OS: 100, 100, 92.2.

OH
59.5
16
MDFS: 32.6; MOS: 59.5; 1, 3, 5 y-DFS: 78.6, 60.9, 40.1; 1, 3, 5 y-OS: 96.5, 92.2, 87.7.

Memeo et al.
LH
NR
25
1, 5, 10 y-DFS: 80, 19, 0; 1, 5, 10 y-OS: 88, 59, 12.

OH
NR
28
1, 5, 10 y-DFS: 60, 23, 9; 1, 5, 10 y-OS: 63, 44, 22.

Lee et al.
LH
22.7
NR
1, 3, 5 y-DFS: 60.5, 53.5, 53.5; 1, 3, 5 y-OS: 95.3, 89.7, 89.7.

OH
44.4
NR
1, 3, 5 y-DFS: 81.5, 66.7, 58.6; 1, 3, 5 y-OS: 93.9, 89.5, 87.3.

Luo et al.
LH
35
20
MDFS: 21.

OH
37
24
MDFS: 18.

Takahara et al.
LH
46.7
NR
1, 3, 5 y-DFS: 83.7, 58.3, 40.7; 1, 3, 5 y-OS: 95.8, 86.2, 76.8.

OH
51.7
NR
1, 3, 5 y-DFS: 79.6, 50.4, 39.3; 1, 3, 5 y-OS: 95.8, 84.0, 70.9.

Han et al.
LH
44.0
43
1, 3, 5 y-DFS: 69.7, 52.0, 44.2; 1, 3, 5 y-OS: 91.6, 87.5, 76.4.

OH
48.7
46
1, 3, 5 y-DFS: 74.7, 49.5, 41.2; 1, 3, 5 y-OS: 93.1, 87.8, 73.2.

Yoon et al.
LH
NR
16
1, 2, 3, 4 y-DFS: 82.0, 63.0, 56.0, 56.0; 1, 2, 3, 4 y-OS: 95.0, 92.0, 86.0, 86.0.

OH
NR
31
1, 2, 3, 4 y-DFS: 88.0, 79.0, 62.0, 62.0; 1, 2, 3, 4 y-OS: 98.0, 93.0, 84.0, 68.0.

Cheung et al.
LH
34.6
36
MDFS: 66.4; MOS: 136; 1, 3, 5 y-DFS: 87.7, 65.8, 52.2; 1, 3, 5 y-OS: 98.9, 89.8, 83.7.

OH
46.6
160
MDFS: 52.4; MOS: 120; 1, 3, 5 y-DFS: 75.2, 56.3, 47.9; 1, 3, 5 y-OS: 94, 79.3, and 67.4.

Sposito et al.
LH
39.3
NR
MDFS: 25.5; MOS: 48.8; 3, 5 y-DFS: 41, 25; 3, 5 y-OS: 75, 38.

OH
44.5
NR
MDFS: 31.7; MOS: 57.8; 3, 5 y-DFS: 44, 11; 3, 5 y-OS: 79, 46.

Jiang et al.
LH
NR
26
MDFS: 17; 5 y-DFS: 44.

OH
NR
30
MDFS: 15; 5 y-DFS: 40.

Komatsu et al.
LH
24.7
NR
3 y-DFS: 50.3; 3 y-OS: 73.4.

OH
NR
3 y-DFS: 29.7; 3 y-OS: 69.2.

Yoon et al.
LH
NR
NR
2 y-DFS: 85.1; 2 y-OS: 100.

OH
NR
NR
2 y-DFS: 83.9; 2 y-OS: 88.8.

Xu et al.
LH
13.8
NR
1, 2 y-DFS: 95.5, 72.9; 1, 2 y-OS: 100, 85.7.

OH
NR
1, 2 y-DFS: 93.5, 81.5; 1, 2 y-OS: 96.3, 86.7.

Follow-up was shown as median month; R: recurrence; DFS: disease-free survival rate; OS: overall survival rate; MDFS: median disease-free survival time; MOS: median overall survival time; y: year; NR: not reported.

(a)

(b)

Figure 4: Forest plot of survival rate: (a) 5-year OS, (b) 5-year DFS.

3.4.5. Publication Bias

The study by Lau et al. was outside the funnel [30], and the remaining representative plots were distributed symmetrically. We believed such publication bias was acceptable in the studies (Figure 5).

Figure 5: Funnel plot of the overall postoperative morbidity.

4. Discussion

This meta-analysis selected and summarized high-quality literature that compared the short- and long-term outcomes of LH and OH for the treatment of HCC. All of the studies had case-matched design and were of high quality according to the modified MINORS scale. For short-term surgical outcomes, LH exhibited advantages in terms of blood loss, hospital stay, overall postoperative morbidity, and mortality, whereas no statistically significant differences were identified regarding operation time. As for oncological outcomes, R0 and survival rates of LH were also not inferior to OH.

To date, there have been several meta-analyses comparing LH to OH for HCC [5–8]. The results have demonstrated that LH is comparable to OH regarding the operation time and postoperative mortality and is associated with less blood loss, as well as a shorter hospital stay (Table 5). Previous meta-analyses included all available research [5, 6, 8] but had some limitations. Pooling of low-quality studies could undermine the strength of results, whereas selectively pooling high-quality NRCTs could strengthen the power of results [10]. Patients’ characteristics and surgical extension have a major impact on the surgical outcomes of hepatectomy. Previous meta-analyses pooled studies, which did not balance the combined factors of tumor size, location, the severity of cirrhosis, and other underlying liver diseases between LH and OH. These factors would have influenced the decision of surgeons and patients and further influenced the major factors of both short- and long-term outcomes. In addition, previous meta-analyses studied LH confined to minor resection. With the accumulation of surgical techniques, major resection of LH has become more commonly performed, but various efficacy and safety concerns for the procedure are warranted. Furthermore, since the publication of previous meta-analyses, several notable clinical observational studies have become available and some of them are from China, where HCC has the highest prevalence in the world [8, 19]. Therefore, our comprehensive meta-analysis will contribute to a more systematic and objective evaluation of the safety and HCC treatment of LH.

Table 5: Previous meta-analyses comparing LH to OH for HCC.

Variables
Zhou
Li
Xiong
Yin

Year
2011
2012
2012
2013

Included studies
10
10
9
15

Total LH numbers
213
244
234
485

Surgical extension
Minor resection
Minor resection
Minor resection
Minor resection

Operation time
NS
NS
NS
NS

Blood loss
Favor LH
Favor LH
Favor LH
Favor LH

Overall morbidity
Favor LH
Favor LH
N/A
Favor LH

Severe complications
N/A
N/A
N/A
N/A

ascites
N/A
N/A
Favor LH
N/A

Liver failure
NS
N/A
Favor LH
N/A

Respiratory complications
NS
N/A
NS
N/A

Mortality
NS
N/A
NS
N/A

Hospital stay
Favor LH
Favor LH
Favor LH
Favor LH

Tumor size
N/A
N/A
N/A
N/A

Margin distance
NS
NS
N/A
NS

R0 resection
N/A
NS
NS
NS

Survival
N/A
N/A
N/A
NS

NS: not significant, N/A: not available.

Several previous studies have demonstrated that LH can be feasible and beneficial for minor resections or nonanatomical resections of peripheral HCC. This is in accordance with our study that showed minor resection of LH with similar operation time and less blood loss than OH. However, minor hepatectomy is insufficient for large lesions or those located in posterosuperior liver segments to ensure an adequate resection margin and eliminate intrahepatic recurrence. Major hepatectomy is more frequently performed with a curative intent for multifocal or large size HCC or those with a high propensity to invade the portal vein branches [41–43]. Laparoscopic major hepatectomy is, because of the same steps and principles used in laparotomy, technically demanding. Mobilization of a heavy as well as fragile organ, excisions of bulky parenchyma, and major vascular dissection with its associated risk of major vessel injury are all considered risky under laparoscopy. As expected, the present study revealed longer operation times in laparoscopic major hepatectomy. Furthermore, unlike minor resections, the blood loss of laparoscopic major hepatectomy was not superior to its open counterpart.

Patients with HCC and concurrent cirrhosis tend to have higher incidences of postoperative complications and of greater severity. Therefore, the decreased complications in the LH group should be our most striking finding. In detail, postoperative ascites and liver failure tend to decrease in LH. Postoperative decompensation after hepatectomy occurs more frequently in patients with liver cirrhosis or portal hypertension, even for limited resections. The minimization of surgical incision and the subsequent preservation of abdominal wall circulation and lymphatic flow can explain fewer ascites and liver failure in LH. Moreover, a small incision limits the evacuation of ascites through the wall and decreases the risk of infection, thus facilitating wound healing. Laparoscopic surgery also decreases the manipulation of abdominal organs and exposure of bowels, which will also contribute to reduced ascites. Since refractory ascites and progressive liver insufficiency are major causes of severe postoperative morbidities, reduced severe postoperative morbidities and mortality could be expected. Major surgery was often thought to be unsuitable for those with severely impaired pulmonary function due to a higher risk of postoperative respiratory complications. Hepatectomy involving multiple systems, especially the water and electrolyte balance, is a major risk factor for medical complications. It was observed from the reviewed studies that respiratory complications were the most common medical complications, mainly pulmonary infection, followed by cardiovascular complications. Improved preservation of liver functions in LH maintains enough albumin synthesis and decreases the pleural effusion. The pain caused by large incisions, as well as the use of tension sutures and abdominal bandages after laparotomy, can make it difficult for patients to cough. Earlier postoperative ambulation in the laparoscopic group also helped to reduce respiratory complications and promote the postoperative recovery of gastrointestinal function. In accordance with other laparoscopic surgeries, LH achieved enhanced postoperative recovery. The postoperative hospitalization of LH decreases by more than two days. This can be explained by the milder surgical trauma of LH and subsequent faster bowel recovery. Less postoperative morbidities also contribute to shorter length of hospitalization.

The oncologic results of LH for HCC remain a matter of debate. Adequate surgical margins independently improve the long-term oncological outcomes. Our analysis showed that LH could achieve enough surgical margins (more than 2 cm) as OH. The 5-year OS and DFS also showed that LH was comparable to OH. However, the results warrant prudent interpretation because of the discrepancies among the pooled studies, such as tumor size, tumor number, and status of the vascular invasion. Other biases lie in other factors including preoperative TACE and postoperative adjuvant therapies. Unfortunately, none of the three major hepatectomy studies can be included in our survival analysis. Thus, well-designed RCTs, that balance all potential factors, preferably containing major resection are needed to confirm our results.

In the process of our research and manuscript review, two similar articles by Sotiropoulos et al. were published [44, 45], which also had limitations. Examples include pooling the low-quality studies together, failing to evaluate extension on surgical outcomes, and one paper only investigating studies conducted in Europe [45]. Besides, since these studies were published, several clinical observational studies have become available. Therefore, our comprehensive meta-analysis will contribute to a more systematic and objective evaluation of this subject.

The major limitation of this study was that all included studies are NRCTs and of retrospective design. NRCTs have potential biases that limit an unequivocal conclusion, even though we exclusively included the case-matched studies to minimize the selection biases. Another limitation is the lack of studies on laparoscopic major hepatectomy. The analysis was based on only three pooled studies. Little is known about how these results would hold for a larger sample size, which is particularly important as a fair number of patients with HCC are treated with open major hepatectomy. In addition, data from several studies are extracted using the methods reported by Hozo et al. and Tierney et al., which are not completely accurate and result in bias. Moreover, it is quite possible that surgical teams undertaking research and publishing their results are more experienced and more skillful than others. Publication bias was inevitable since one plot was outside the funnel. The bias would be overcome only with the collection of more reports.

5. Conclusions

This meta-analysis has highlighted that LH can be safely performed in select patients and improves surgical outcomes when compared to OH. The data indicate that laparoscopic minor hepatectomy is acceptable with less blood loss, less postoperative morbidity, shorter hospitalization, and comparable operation times and oncological outcomes. The role of laparoscopic major hepatectomy is promising in terms of decreasing postoperative morbidity and recovery, but the technique also has drawbacks in prolonged operation time. Given the heterogeneity of the patient groups, the limitations of study design, and the small sample size, it is likely that patients have potential to benefit from LH, but further well-designed studies are needed to accurately select them.

Abbreviations

LH: | Laparoscopic hepatectomy
OH: | Open hepatectomy
HCC: | Hepatocellular carcinoma
NRCT: | Nonrandomized comparative study
RCT: | Randomized controlled trial
MINORS: | Methodological Index for Nonrandomized Studies
RR: | Risk ratio
WMD: | Weighted mean difference
SD: | Standard deviation
OS: | Overall survival rate
DFS: | Disease-free survival rate
HR: | Hazard ratio.

Conflicts of Interest

The authors declare that they have no conflicts of interest.

Authors’ Contributions

Ke Chen designed the study; Yu Pan and Xiao-long Liu collected literature and conducted the analysis of pooled data; Hendi Maher helped to draft the manuscript; Ke Chen and Xue-yong Zheng wrote the manuscript; Xue-yong Zheng proofread and revised the manuscript. All authors have approved the version to be published.

Supplementary Materials

Table of modified MINORS score of studies with score < 12. (Supplementary Materials)

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