He S, Yu TN, Cao JS, Zhou XY, Chen ZH, Jiang WB, Cai LX, Liang X. Laparoscopic vs open radical resection in management of gallbladder carcinoma: A systematic review and meta-analysis. World J Clin Cases 2023; 11(27): 6455-6475 [PMID: 37900219 DOI: 10.12998/wjcc.v11.i27.6455]
Corresponding Author of This Article
Xiao Liang, MD, PhD, Attending Doctor, Professor, Surgeon, Department of General Surgery, Sir Run-Run Shaw Hospital of Zhejiang University School of Medicine, No. 3 East Qingchun Road, Hangzhou 310016, Zhejiang Province, China. srrshlx@zju.edu.cn
Research Domain of This Article
Surgery
Article-Type of This Article
Meta-Analysis
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Shilin He, Tu-Nan Yu, Jia-Sheng Cao, Xue-Yin Zhou, Wen-Bin Jiang, Liu-Xin Cai, Xiao Liang, Department of General Surgery, Sir Run-Run Shaw Hospital of Zhejiang University School of Medicine, Hangzhou 310016, Zhejiang Province, China
Xue-Yin Zhou, School of Medicine, Wenzhou Medical University, Wenzhou 325035, Zhejiang Province, China
Zhe-Han Chen, The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou 310053, Zhejiang Province, China
Zhe-Han Chen, Department of Hepatobiliary Surgery, Fuyang First People’s Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou 311400, Zhejiang Province, China
Author contributions: He S acquired, analyzed, and interpreted the data, drafted the manuscript, and approved the final manuscript; Yu TN, Cao JS, and Cai LX revised the manuscript and approved the final manuscript; Zhou XY and Chen ZH interpreted the data, revised the manuscript, and approved the final manuscript; Jiang WB acquired and interpreted the data, and approved the final manuscript; Liang X conceptualized and designed the study, critically revised the manuscript, and approved the final manuscript.
Conflict-of-interest statement: The authors deny any conflict of interest for this article.
PRISMA 2009 Checklist statement: The authors have read the PRISMA 2009 Checklist, and the manuscript was prepared and revised according to the PRISMA 2009 Checklist.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Xiao Liang, MD, PhD, Attending Doctor, Professor, Surgeon, Department of General Surgery, Sir Run-Run Shaw Hospital of Zhejiang University School of Medicine, No. 3 East Qingchun Road, Hangzhou 310016, Zhejiang Province, China. srrshlx@zju.edu.cn
Received: May 20, 2023 Peer-review started: May 20, 2023 First decision: June 15, 2023 Revised: June 29, 2023 Accepted: July 24, 2023 Article in press: July 24, 2023 Published online: September 26, 2023
Abstract
BACKGROUND
Radical resection offers the only hope for the long-term survival of patients with gallbladder carcinoma (GBC) above the T1b stage. However, whether it should be performed under laparoscopy for GBC is still controversial.
AIM
To compare laparoscopic radical resection (LRR) with traditional open radical resection (ORR) in managing GBC.
METHODS
A comprehensive search of online databases, including Medline (PubMed), Cochrane Library, and Web of Science, was conducted to identify comparative studies involving LRR and ORR in GBCs till March 2023. A meta-analysis was subsequently performed.
RESULTS
A total of 18 retrospective studies were identified. In the long-term prognosis, the LRR group was comparable with the ORR group in terms of overall survival and tumor-free survival (TFS). LRR showed superiority in terms of TFS in the T2/tumor-node-metastasis (TNM) Ⅱ stage subgroup vs the ORR group (P = 0.04). In the short-term prognosis, the LRR group had superiority over the ORR group in the postoperative length of stay (POLS) (P < 0.001). The sensitivity analysis showed that all pooled results were robust.
CONCLUSION
The meta-analysis results show that LRR is not inferior to ORR in all measured outcomes and is even superior in the TFS of patients with stage T2/TNM Ⅱ disease and POLS. Surgeons with sufficient laparoscopic experience can perform LRR as an alternative surgical strategy to ORR.
Core Tip: Using laparoscopic surgery to treat gallbladder carcinoma (GBC) is still controversial. This is the first meta-analysis to directly compare laparoscopic radical resection and open radical resection in GBC. Unlike previous similar meta-analyses, we excluded interference from simple cholecystectomy cases in our study and conducted a subgroup analysis. We also tested the publication bias and conducted a sensitivity analysis.
Citation: He S, Yu TN, Cao JS, Zhou XY, Chen ZH, Jiang WB, Cai LX, Liang X. Laparoscopic vs open radical resection in management of gallbladder carcinoma: A systematic review and meta-analysis. World J Clin Cases 2023; 11(27): 6455-6475
Gallbladder carcinoma (GBC) carries one of the most dismal prognoses among all types of malignancies. The 5-year survival rates range from 5% to 15%[1,2]. The most common pathological type of GBC is adenocarcinoma, which accounts for more than 80% of all GBCs[3,4]. Others types include adenosquamous carcinoma, squamous carcinoma, neuroendocrine carcinoma, and so forth. It has a remarkable propensity to spread early by invading the liver and other adjacent organs directly or metastasizing to lymph nodes. Thus, it is generally believed that simple cholecystectomy (SC) is not sufficient for GBC staged T1b and above. Radical resection, which includes partial hepatectomy and lymph node dissection, offers the only hope for long-term survival[5,6].
Systemic therapy has consistently played an essential role in treating GBC and biliary tract cancer (BTC), considering the low resection rate at the diagnosis. The main chemotherapy regimen employed for advanced GBC, even today, remains cisplatin combined with gemcitabine (CisGem)[7]. In the last decade, immune checkpoint inhibitors (ICIs) have made major breakthroughs in the field of cancer treatment and changed the treatment pattern of several malignant tumors, especially malignancies with deficient mismatch repair, high tumor mutational burden, or high microsatellite instability[8-10]. However, the role of ICIs in BTC needs further exploration. Also, their combination with other anti-cancer drugs (chemotherapy, targeted agents, etc.) may be a more promising direction[10-15]. Additionally, researchers are actively investigating the relationship between ICIs and other therapeutic targets, such as breast cancer susceptibility genes (BRCA) 1/2 mutations (BRCAm), to provide patients with more personalized and precise treatment[16].
Laparoscopic surgery has been widely performed in most cancers, including colon, gastric, and liver cancers. Compared with traditional open surgery, laparoscopic radical surgery shows the advantage of minimal invasion and achieves satisfactory long-term survival[17-20]. However, for a long time, laparoscopic surgery has only been recommended for treating benign gallbladder diseases, staging and biopsying of GBC, or resecting GBC in very early stages (Tis and T1a)[21-23]. GBC with T1b stage or above has always been considered contraindicated, requiring a radical resection. In recent years, many surgeons have tried to apply laparoscopic technology to manage GBCs. Several meta-analyses have discussed this issue and reached optimistic conclusions[24-27]. However, whether laparoscopic radical resection (LRR) is feasible in treating GBC staged T1b and above still has not been fully demonstrated because the studies included in these meta-analyses contained several SC cases. Thus, a new meta-analysis focusing on the feasibility of LRR by excluding all SC cases should be performed.
MATERIALS AND METHODS
Search strategy and study selection
A systematic review of the published studies till March 2023 was performed to screen studies comparing the outcomes of patients who underwent LRR vs open radical resection (ORR) for GBCs. We searched the abstracts in PubMed, Cochrane Library, and Web of Science using the following keywords: Laparoscopic OR minimally invasive AND gallbladder cancer OR GBC OR gallbladder neoplasm. Searches were limited to human studies and English-language publications. The citation lists of retrieved studies were manually filtered to identify other studies. Two researchers independently searched for studies and compared the results.
Study selection
Eligible studies were required to meet the following criteria: (1) The study must have a comparative design and evaluate LRR and ORR for GBC; and (2) the study should be a human study published in English.
The study was excluded from the analysis for the following reasons: (1) Case report or case series studies; (2) studies enrolling patients who just underwent laparoscopic simple cholecystectomy (LSC) or whose surgical method was unclear; and (3) studies including other tumors, such as intrahepatic bile duct cancer, in which GBC data could not be extracted separately. The literature search and selection strategy are demonstrated in Figure 1. The modified Newcastle-Ottawa scale was used to assess the quality of included studies[28].
Figure 1
Search strategy and identification of studies for the systematic review and meta-analysis.
Data extraction and outcome measures
The data extraction was performed independently by two authors. The following details were extracted: Study period, study design, country/region, number of patients, sex, age, type of surgery, tumor stage, operation time, blood loss, complications, postoperative length of stay (POLS), resection margin, and so forth.
The primary outcomes were overall survival (OS) and tumor-free survival (TFS). If the hazard ratio (HR) and 95% confidence interval (CI) of survival were not reported, they were extracted from the survival curve using Engauge Digitizer 11.1 software. Subsequently, the HR and 95%CI were calculated and converted into lnHR and its standard error for further analysis[29]. The secondary outcomes included the following: The number of lymph nodes harvested (No. LNH), operation time, blood loss, R0 resection rate, POLS, and complication rate. In cases where the aforementioned information was a a median (range) for a continuous variable, it was converted into the mean ± SD using established methods[30,31]. Two authors independently extracted and compared the data to eliminate the errors. Due to unavailable data, not all included studies could participate in every outcome analysis.
Statistical analysis
The studies from which valid data could be extracted were included in the final meta-analysis. For dichotomous data, the odds ratio (OR) and 95%CI were calculated; for continuous data, the mean difference (MD) and 95%CI were calculated. For survival data, we calculated HR and 95%CI. The χ2 and I2 statistic were used to measure heterogeneity. For example, the χ2P < 0.05 or I2 > 50% indicated significant heterogeneity. In this case, a random-effects model was adopted when appropriate; otherwise, a fixed-effects model was used. All meta-analyses were performed using the statistical software [Review Manager (RevMan) version 5.3, Copenhagen, Denmark: The Nordic Cochrane Centre, The Cochrane Collaboration; 2014]. A P value < 0.05 indicated a statistically significant difference.
Risk of bias
Begg’s and Egger’s tests were used to evaluate potential publication bias quantitatively. A P value or corrected P value of < 0.05 in the test indicated the presence of significant statistical publication bias. The results are shown in Table 1. Besides, sensitivity analysis was conducted to assess the stability of the pooled results of major measured outcomes. The results of the sensitivity analysis are presented in Figure 2. Begg’s test, Egger’s test, and sensitivity analysis were conducted using Stata software (version 17.0).
Figure 2 Results of sensitivity analysis on major measured outcomes.
A: Number of lymph nodes harvested; B: Operation time; C: Intraoperative blood loss; D: Postoperative length of stay; E: Postoperative complications; F: Postoperative complications (Clavien-Dindo 3-4); G: R0 resection rate; H: Overall survival; I: Tumor-free survival.
Table 1 Publication bias test of major measured outcomes.
No. of studies
No. of patients
Egger's test
Begg's test (continuity corrected)
LRR
ORR
t
P > |t|
z
P > |z|
No. LNH
17
799
1209
-5.1
< 0.001
0.37
0.711
Operation time
16
564
764
1.57
0.139
0.86
0.392
Blood loss
14
489
689
-2.18
0.050
1.86
0.063
POLS
17
799
1209
-3.03
0.008
0.04
0.967
R0 rate
8
1609
1705
1.64
0.162
0.00
1.000
Complications
15
511
703
-1.67
0.119
1.29
0.198
Complications (Clavien-Dindo 3-4)
8
244
245
-1.85
0.162
0.73
0.462
OS
15
1299
1936
0.3
0.767
0.68
0.499
TFS
10
339
338
-1.04
0.329
0.36
0.721
Subgroup analysis
Subgroup analysis was conducted to reduce interference from tumor stage and other factors. Based on the available data, we found that fewer data on T1/tumor-node-metastasis (TNM) Ⅰstage and T3/TNM Ⅲ stage could be extracted. Therefore, we conducted a subgroup analysis for T1/TNM Ⅰ + T2/TNM Ⅱ stage, T2/TNM Ⅱ stage, and T2/TNM Ⅱ + T3/TNM Ⅲ stage. In addition, we also conducted a subgroup analysis of the data after propensity score matching (PSM).
RESULTS
Study selection and characteristics
Eighteen retrospective studies were identified after screening based on the inclusion criteria and assessing the full text of potentially eligible studies[32-49]. The characteristics and quality evaluation of the 18 included studies for meta-analysis are summarized in Table 2. These studies included 3513 patients with GBC who underwent surgery with curative intention, of which 1422 were in the LRR group and 2091 in the ORR group. The details about these patients are listed in Table 3. One study[33] included 12 cases of LSC; we retained this study and only included data from its T2 and T3 subgroups comprising no LSC cases. Another study[47] initially included eight LSC cases. However, the laparoscopic and open surgery groups were reduced to four cases following PSM. This adjustment had less impact on the analysis results, thus warranting the retention of this study. The data after PSM was available in 6 of the 18 studies.
Table 2 Characteristics of included comparative studies.
OS and TFS: The OS data were available in 1615 studies, and no significant heterogeneity existed [χ2 = 17.31, df = 15 (P = 0.30), I2 = 13%]. Therefore, a fixed-effects model was used. The result showed no difference in OS between the LRR and ORR groups (HR: 0.92, 95%CI: 0.80 to 1.05, P = 0.22; Figure 3A).
Figure 3 Forest plots of pooled hazard ratio for survival outcomes.
A: Overall survival (OS); B: Tumor-free survival (TFS); C: OS after propensity score matching (PSM); D: TFS after PSM. LRR: Laparoscopic radical resection; ORR: Open radical resection; CI: Confidence interval.
The TFS data were available in 10 studies, and no significant heterogeneity existed [χ2 = 9.32, df = 9 (P = 0.41), I2 = 3%]. Therefore, a fixed-effects model was used. The result showed no difference in TFS between the LRR and ORR groups (HR: 0.93, 95%CI: 0.66 to 1.31, P = 0.70; Figure 3B).
OS and TFS after PSM: The OS data after PSM were available in five studies, and no significant heterogeneity existed [χ2 = 1.15, df = 4 (P = 0.89), I2 = 0%]. Therefore, a fixed-effects model was used. The result showed no difference in OS between the LRR and ORR groups (HR: 0.71, 95%CI: 0.39 to 1.30, P = 0.27; Figure 3C).
The TFS data after PSM were available in four studies, and no significant heterogeneity existed [χ2 = 0.96, df = 3 (P = 0.81), I2 = 0%]. Therefore, a fixed-effects model was used. The result showed no difference in TFS between the LRR and ORR groups (HR: 1.00, 95%CI: 0.63 to 1.57, P = 0.99; Figure 3D).
OS and TFS in T2/TNM Ⅱ subgroup: The OS data of patients with stage T2/TNM Ⅱ disease were available in seven studies, and no significant heterogeneity existed [χ2 = 3.66, df = 6 (P = 0.72), I2 = 0%]. Therefore, a fixed-effects model was used. The result showed no difference in OS between the LRR and ORR groups for the T2/TNM Ⅱ subgroup (HR: 0.94, 95%CI: 0.53 to 1.65, P = 0.83; Figure 4A).
Figure 4 Forest plots of pooled hazard ratio for survival outcomes in subgroup analysis.
A: Overall survival (OS) in the T2/tumor-node-metastasis (TNM) Ⅱ subgroup; B: Tumor-free survival (TFS) in the T2/TNM Ⅱ subgroup; C: OS in the T1/TNM Ⅰ + T2/TNM Ⅱ subgroup; D: TFS in the T1/TNM Ⅰ + T2/TNM Ⅱ subgroup; E: OS in the T2/TNM Ⅱ + T3/TNM Ⅲ subgroup; F: TFS in the T2/TNM Ⅱ + T3/TNM Ⅲ subgroup. LRR: Laparoscopic radical resection; ORR: Open radical resection; CI: Confidence interval.
The TFS data of patients with stage T2/TNM Ⅱ disease were available in five studies, and no significant heterogeneity existed [χ2 = 4.12, df = 4 (P = 0.39), I2 = 3%]. Therefore, a fixed-effects model was used. The LRR group showed a better TFS than the ORR group for the T2/TNM Ⅱ subgroup (HR: 0.50, 95%CI: 0.26 to 0.96, P = 0.04; Figure 4B).
OS and TFS in T1/TNM Ⅰ + T2/TNM Ⅱ subgroup: The OS data of patients with stage T1/TNM Ⅰ or T2/TNM Ⅱ disase were available in 11 studies, and no significant heterogeneity existed [χ2 = 7.06, df = 11 (P = 0.79), I2 = 0%]. Therefore, a fixed-effects model was used. The result showed no difference in OS between the LRR and ORR groups for the T1/TNM Ⅰ + T2/TNM Ⅱ subgroup (HR: 1.35, 95%CI: 0.95 to 1.92, P = 0.09; Figure 4C).
The TFS data of patients with stage T1/TNM Ⅰ or T2/TNM Ⅱ disease were available in seven studies, and no significant heterogeneity existed [χ2 = 8.23, df = 6 (P = 0.22), I2 = 27%]. Therefore, a fixed-effects model was used. A significant difference was detected in TFS between the LRR and ORR groups for the T1/TNM Ⅰ or T2/TNM Ⅱ subgroup (HR: 0.83, 95%CI: 0.54 to 1.27, P = 0.39; Figure 4D).
OS and TFS in T2/TNM Ⅱ + T3/TNM Ⅲ subgroup: The OS data of patients with stage T2/TNM Ⅱ or T3/TNM Ⅲ disease were available in nine studies, and no significant heterogeneity existed [χ2 = 4.56, df = 10 (P = 0.92), I2 = 0%]. Therefore, a fixed-effects model was used. The result showed no difference in OS between the LRR and ORR groups for the T2/TNM Ⅱ + T3/TNM Ⅲ subgroup (HR: 0.82, 95%CI: 0.64 to 1.05, P = 0.12; Figure 4E).
The TFS data of patients with stage T2/TNM Ⅱ or T3/TNM Ⅲ disease was available in seven studies, and no significant heterogeneity existed [χ2 = 7.79, df = 6 (P = 0.25), I2 = 23%]. Therefore, a fixed-effects model was used. A significant difference was detected in TFS between the LRR and ORR groups for the T2/TNM Ⅱ + T3/TNM Ⅲ subgroup (HR: 0.81, 95%CI: 0.52 to 1.24, P = 0.32; Figure 4F).
Short-term outcomes
Number of LNH: The data regarding the No. LNH were reported in 17 studies. Significant heterogeneity existed between these studies [χ2 = 131.34, df = 16 (P < 0.001), I2 = 88%]. Therefore, a random-effects model was used. The results showed no significant difference in the No. LNH between the LRR and ORR groups (MD: -0.73, 95%CI: -1.87 to 0.41, P = 0.21; Figure 5A).
Figure 5 Forest plots of pooled odds ratio or weighted mean difference of short-term outcomes.
A: Number of lymph nodes harvested; B: Operation time; C: Intraoperative blood loss; D: Postoperative length of stay; E: Postoperative complications; F: Postoperative complications (Clavien-Dindo 3-4); G: R0 margin rate; H: Early-stage rate (≤ T2/tumor-node-metastasis Ⅱ stage). LRR: Laparoscopic radical resection; ORR: Open radical resection; CI: Confidence interval.
The data regarding the No. LNH after PSM were reported in six studies. Significant heterogeneity was found between these studies [χ2 = 78.43, df = 5 (P < 0.001); I2 = 94%]. Therefore, a random-effects model was used. The results showed no significant difference in the No. LNH between the LRR and ORR groups (MD: -1.52, 95%CI: -4.20 to 1.15, P = 0.26; Figure 6A).
Figure 6 Forest plots of pooled odds ratio or weighted mean difference of short-term outcomes after propensity score matching.
A: Number of lymph nodes harvested; B: Operation time; C: Intraoperative blood loss; D: Postoperative length of stay; E: Postoperative complications; F: Postoperative complications (Clavien-Dindo 3-4). LRR: Laparoscopic radical resection; ORR: Open radical resection; CI: Confidence interval.
Operation time: The data on operation time were reported in 16 studies. Significant heterogeneity existed between these studies [χ2 = 288.26, df = 15 (P < 0.001), I2 = 95%]. Therefore, a random-effects model was used. The results showed no significant difference in the operation time between the LRR and ORR groups (MD: 7.72, 95%CI: -16.28 to 31.72, P = 0.53; Figure 5B).
The data on operation time after PSM were reported in six studies. Significant heterogeneity existed between these studies [χ2 = 81.27, df = 5 (P < 0.001), I2 = 94%]. Therefore, a random-effects model was used. The results showed no significant difference in the operation time between the LRR and ORR groups (MD: 22.69, 95%CI: -12.93 to 58.31, P = 0.21; Figure 6B).
Intraoperative blood loss: The data on intraoperative blood loss were reported in 14 studies. Significant heterogeneity existed between these studies [χ2 = 516.12, df = 13 (P < 0.001), I2 = 97%]. Therefore, a random-effects model was used. The LRR group showed lesser intraoperative blood loss than the ORR group (MD: -60.58, 95%CI: -102.94 to -18.23, P = 0.005; Figure 5C).
The data on intraoperative blood loss after PSM were reported in four studies. Significant heterogeneity existed between these studies [χ2 = 237.8, df = 3 (P < 0.001), I2 = 99%]. Therefore, a random-effects model was used. The results showed no significant difference in the intraoperative blood loss between the LRR and ORR groups (MD: -94.71, 95%CI: -262.26 to 72.83, P = 0.27; Figure 6C).
POLS: The data regarding POLS were reported in 17 studies. Significant heterogeneity existed between these studies [χ2 = 212.98, df = 16 (P < 0.001), I2 = 92%]. Therefore, a random-effects model was used. The LRR group showed a shorter POLS than the ORR group (MD: -3.31, 95%CI: -4.38 to -2.24, P < 0.001; Figure 5D).
The data regarding POLS after PSM were reported in six studies. Significant heterogeneity was found between these studies [χ2 = 139.03, df = 5 (P < 0.001);, I2 = 96%]. Therefore, a random-effects model was used. The LRR group showed a shorter POLS than the ORR group (MD: -4.11, 95%CI: -6.10 to 2.12, P < 0.001; Figure 6D).
Complications: The data on complications were reported in 15 studies. No significant heterogeneity existed [χ2 = 7.68, df = 14 (P = 0.91); I2 = 0%]. Therefore, a fixed-effects model was used. The LRR group showed a lower complication rate than the ORR group (OR: 0.69, 95%CI: 0.49 to 0.96, P = 0.03; Figure 5E).
The data on complications after PSM were reported in six studies. No significant heterogeneity existed [χ2 = 18.04, df = 15 (P = 0.26), I2 = 17%]. Therefore, a fixed-effects model was used. The results showed no significant difference in the complications between the LRR and ORR groups (OR: 1.00, 95%CI: 0.78 to 1.28, P = 1.00; Figure 6E).
Complications (Clavien-Dindo 3-4): The data on complications (Clavien-Dindo 3-4) were reported in eight studies. No significant heterogeneity existed [χ2 = 3.18, df = 4 (P = 0.53), I2 = 0%]. Therefore, a fixed-effects model was used. The results showed no significant difference in the complications (Clavien-Dindo 3-4) between the LRR and ORR groups (OR: 0.59, 95%CI: 0.26 to 1.32, P = 0.20; Figure 5F).
The data on complications (Clavien-Dindo 3-4) after PSM were reported in five studies. No significant heterogeneity existed [χ2 = 0.55, df = 1 (P = 0.46); I2 = 0%]. Therefore, a fixed-effects model was used. The results showed no significant difference in the complications (Clavien-Dindo 3-4) between the LRR and ORR groups (OR: 1.00, 95%CI: 0.24 to 4.19, P = 1.00; Figure 6F).
R0 resection rate: The data regarding the R0 resection rate were reported in eight studies. No significant heterogeneity existed [χ2 = 1.77, df = 6 (P = 0.94), I2 = 0%]. Therefore, a fixed-effects model was used. The LRR group showed a significantly higher R0 resection rate compared with the ORR group (OR: 1.23, 95%CI: 1.01 to 1.50, P = 0.04; Figure 5G). The data of the R0 resection rate after PSM were not enough for pooled analysis.
Early-stage rate
We defined the T1-2 stage and TNM Ⅰ-Ⅱ stage as the early-stage group, and the T3-4 stage and TNM Ⅲ-Ⅳ stage as the late-stage group. Of the 18 studies included, 9 comprised only early-stage or late-stage cases. We included the remaining nine studies for analysis. Significant heterogeneity existed between these studies [χ2 = 17.40, df = 8 (P = 0.03), I2 = 54%]. Therefore, a random-effects model was used. The LRR group showed a significantly higher early-stage rate compared with the ORR group (OR: 1.54, 95%CI: 1.08 to 2.18, P = 0.02; Figure 5H).
Evaluation of publication bias and sensitivity analysis
Egger’s test, Begg’s test, and sensitivity analysis were performed to evaluate major measured outcomes, including the No. LNH, operation time, blood loss, POLS, complications, complications (Clavien-Dindo 3-4), R0 resection rate, OS, and TFS. A remarkable asymmetry was detected using Egger’s test in the No. LNH, operation time, and POLS; however, no publication bias was detected using Begg’s test in all measured outcomes. The results of Egger’s and Begg’s tests are presented in Table 1. The sensitivity analysis showed that the pooled results of all of the major outcomes were stable and robust. The results of the sensitivity analysis are presented in Figure 6.
DISCUSSION
In the analysis of long-term prognosis, the LRR group was comparable with the ORR group in terms of OS and TFS. The same result was obtained even after PSM. Then, the subgroup analysis on T2/TNM Ⅱ stage, T1/TNM Ⅰ + T2/TNM Ⅱ stage, and T2/TNM Ⅱ + T3/TNM Ⅲ stage was performed. The results showed that the LRR group had a superiority over the ORR group in terms of TFS only in the T2/Ⅱ stage subgroup (P = 0.04). In the analysis of short-term prognosis, the LRR group had superiority over the ORR group in terms of blood loss (P = 0.005), POLS (P < 0.001), complication rate (P = 0.03), and R0 resection rate (P = 0.04). After PSM, the advantage in the POLS persisted (P < 0.001), but the differences in the blood loss (P = 0.27) and complication rate (P = 0.29) were no longer significant. The R0 resection rate could not be analyzed after PSM due to the unavailability of data. The LRR and ORR groups did not exhibit significant differences in other short-term outcomes, such as No. LNH, surgical time, and complication rate (Clavien-Dindo 3-4), regardless of whether PSM was done. Although Egger’s and Begg’s tests indicated the presence of publication bias, the sensitivity analysis confirmed the stability and robustness of all pooled results.
In recent years, several meta-analyses have been published comparing laparoscopic and open surgery for treating GBC, and similar results were obtained[24-27]. However, we believed that conducting this meta-analysis was necessary because it significantly differed from previous studies. First, all previous meta-analyses included numerous studies with a substantial number of SC cases. For example, the study by Jang et al[50] included 197 cases. However, in their study, 94 cases in the laparoscopic group and 30 in the open surgery group just underwent SC, and only 73 cases in the open surgery group underwent ORR. This study aimed to explore the feasibility of LSC for T1 GBC. In the study performed by Goetze and Paolucci[51], 837 patients were included. A total of 492 patients underwent LSC, 200 underwent open surgery, and 142 initially underwent LSC using the primary access technique, but required conversion to open surgery. Furthermore, among the 300 patients who underwent re-resection, the stratification was based on the primary surgical approach, and whether LRR was performed was not clearly mentioned. Based on the content and time of the research, it was highly likely that the re-resection procedures were carried out as open surgery. This study aimed to explore the impact of the primary access technique (laparoscopy vs primary open surgery) on the prognosis of GBCs. The aforementioned two studies were included in all of the previous meta-analyses and made important contributions to the pooled results because of their large sample sizes. Similar situations existed in many other included studies[52-61], and they did not discuss the impact of the approach of radical resection on the prognosis of GBC. Therefore, these studies were not included based on our inclusion criteria. This is the biggest difference between our meta-analysis and the previous meta-analyses. Second, we analyzed the results of TFS, which were not used in the previous meta-analyses. The results of the overall recurrence rate were pooled in the meta-analysis performed by Lv et al[26] and Nakanishi et al[27]. However, we presumed that it was unreasonable to directly pool the overall recurrence rate results because the follow-up times of the included studies were not the same and the HR used in our study was more reasonable. Third, we analyzed the data after PSM to minimize the influence of other factors on the results, which was not reported in the previous meta-analyses. Fourth, we pooled the staging data and found that the cases included in the LRR group had an earlier stage than those in the ORR group. Tumor staging is one of the most important factors affecting the prognosis, suggesting that our interpretation of the overall results should be conservative and that we should pay more attention to subgroup analysis.
Laparoscopic surgery has been thought to worsen the prognosis of GBC, which was first described in the 1990s[62-64]. Since then, it has been controversial, and the focus is on the possible port-site recurrence and peritoneal metastasis after laparoscopic surgery, which was considered to be associated with intraoperative gallbladder perforation and pneumoperitoneum and suggested a poor prognosis[65-67]. The submucosa of the gallbladder wall is absent, and the muscularis propria is extremely thin. Thus, gallbladder perforation is more likely to occur in laparoscopic surgery. Around the 2000s, the gallbladder perforation rate in laparoscopic surgery was reported to be 20%-36%[64,67-69]. However, currently, gallbladder perforation is not as common as earlier, which may be attributed to the improvement in the operation skills of the surgeons. Of the 18 studies included in our meta-analysis, only the study by Feng et al[33] reported perforations caused by gallbladder decompression due to incarcerated gallstones or severe inflammation, and the incidence showed no difference between the laparoscopic and open surgery groups. Besides, the routine use of retrieval bags avoided the direct contact between the surgical specimen and the extraction port, significantly reduced the risk of port-site metastasis[64]. In the 1990s, the incidence of port-site metastases in incidental GBC was reported as high as 17%[70]. However, the incidence decreased to 10% in a recent systematic review, and the recurrence rate of incisions after open surgery remained at about 7%[71]. Further, the incidence of peritoneal carcinomatosis was even higher in the ORR group than in the LRR group in the study by Vega et al[38].
Another concern is about whether laparoscopic surgery is competent for the radical resection of GBC, which includes partial hepatectomy (wedge resection/Ⅳb + Ⅴ segment resection) and lymph node dissection. In the past, such a complicated surgery was not appropriate to be performed in laparoscopy. However, the development of laparoscopic surgery for other cancers has changed this view. Numerous reports have been published regarding the use of laparoscopic techniques in complex liver resections, including procedures like right hemi-hepatectomy, caudate lobe resection, and so forth. These reports consistently demonstrate improved short-term prognosis and comparable long-term survival[72-74]. The laparoscopic techniques have also been reported in live liver donation[75,76]. More extensive lymph node dissection is performed under laparoscopy for treating gastric cancer[17,77]. Thus, from a purely technical perspective, the current laparoscopic techniques can fully meet the requirements of radical resection for elective GBC, and it seems that LRR should no longer be considered a contraindication for GBC.
The treatment of GBC will be a comprehensive pattern based on surgery, with chemotherapy, immunotherapy, and targeted therapy combined. And it is developing towards the trend of being minimally invasive, precise, and individualized. In this study, LRR not only provided satisfactory survival, but also demonstrated the advantages of minimally invasive and enhanced postoperative recovery. It may inevitably play a more critical role in treating of GBC. In addition, the rapid development of targeted agents and immunotherapy may provide more treatment options for GBC.
This meta-analysis had some limitations. First, all included studies were retrospective, and no randomized controlled or prospective studies were included. Second, significant heterogeneities were found in some analyses, the reasons for which were difficult to find; we could only reduce their impact by choosing random-effects models. Third, we found using Egger’ test that a publication bias might exist, which was difficult to eliminate. Fourth, the estimated HR extracted from the survival curve was rough and might introduce bias. Fifth, related confounding factors were difficult to extract from the study, and few studies were included in the subgroup analysis of staging and the analysis after PSM. Sixth, most of the included studies did not report detailed adjuvant therapy data, therefore it was difficult to judge the impact of adjuvant therapy on long-term prognosis. This study was not impeccable; however, it truly described the current state in this field and provided reasonable support for the further exploration of LRR in treating GBC.
CONCLUSION
Our analysis enrolled a large number of comparative studies. This is the first study to compare LRR and ORR in treating GBC. While excluding the interference of SC cases, the data after PSM was analyzed for the first time. The results of the meta-analysis showed that LRR was not inferior to ORR in all measured outcomes and even showed superiority in the TFS of patients with stage T2/TNM Ⅱ disease and POLS. Surgeons with sufficient laparoscopic experience can perform LRR as an alternative surgical strategy to ORR. This may not be the final conclusion, and a more comprehensive meta-analysis is necessary.
ARTICLE HIGHLIGHTS
Research background
Laparoscopic surgery has been widely used in the treatment of a variety of tumors, but it is still controversial in the treatment of gallbladder cancer. This is the first meta-analysis to compare laparoscopic radical resection (LRR) and open radical resection (ORR) in gallbladder carcinoma (GBC) directly.
Research motivation
This study compared LRR with traditional ORR in the management of GBC. It aimed to resolve the disputes faced by LRR and provide support for further research.
Research objectives
This study aimed to clarify the feasibility of LRR in GBC treatment, and encourage more surgeons to further carry out research on LRR, and move the minimally invasive treatment of gallbladder cancer forward.
Research methods
We systematically reviewed the literature on the LRR and ORR in GBC, and integrated the available data for meta-analysis. The Begg’s test and Egger’s test were used to assess potential publication bias, and sensitivity analysis was performed to evaluate the stability of the results.
Research results
This study found that the LRR group was comparable with the ORR group in long-term and short-term prognosis, and even showed advantages in some aspects, such as tumor-free survival (TFS) in the T2/tumor-node-metastasis (TNM) Ⅱ stage subgroup and postoperative length of stay (POLS). Although there is still a lack of support from randomized controlled trials (RCTs), this result will encourage surgeons to conduct further and more in-depth research.
Research conclusions
The meta-analysis results showed that LRR was not inferior to ORR in all measured outcomes and even showed superiority in the TFS of patients with stage T2/TNM Ⅱ disease and POLS. It is the first meta-analysis that excluded interference from simple cholecystectomy cases, and it is also the first time to conduct a subgroup analysis of the data after propensity score matching.
Research perspectives
LRR will inevitably play a more important role in the treatment of GBC, considering its minimally invasive characteristics and the advantage of enhanced postoperative recovery. But it requires further research, such as RCT or research on the combination of LRR and adjuvant therapy.
ACKNOWLEDGEMENTS
We are grateful to our colleagues for their assistance in checking the data of the studies.
Footnotes
Provenance and peer review: Unsolicited article; Externally peer reviewed.
Peer-review model: Single blind
Specialty type: Medicine, research and experimental
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