Laparoscopic versus open treatment of gallbladder cancer: A systematic review and meta-analysis.

BACKGROUND: The aim of this review was to evaluate the effect of laparoscopic surgery on the treatment of patients with gallbladder cancer (GBC).
METHODS: : A comprehensive search of Medline and Cochrane Library was conducted to identify relevant articles. A meta-analysis was subsequently performed.
RESULTS: : A total of 20 studies including 1217 patients met the inclusion criteria. The meta-analysis showed that the 5-year survival rate was significant higher in laparoscopic group than open group (48.4% vs. 38.5%; odds ratio [OR], 1.63; 95% confidence interval [CI], 1.22-2.19; P = 0.001). Although the scar recurrence rate was significant higher in laparoscopic group than open group (7.1% vs. 4.0%; OR, 2.10; 95% CI, 1.11-3.96; P = 0.02), the overall recurrence rates between two groups were not significant different (44.8% vs. 42.2%; OR, 0.86; 95% CI, 0.64-1.14; P = 0.29). In addition, compared with open extended cholecystectomy (EC), laparoscopic EC (LEC) was associated with less intraoperative blood loss, shorter post-operative hospital stays and insignificant less complication rate (10.0% vs. 18.3%; OR, 0.51; 95% CI, 0.15-1.73; P = 0.28).
CONCLUSION: Laparoscopic simple cholecystectomy does not lead to a worse prognosis when applied on patients with GBC. LEC can be performed in specialised expert centres on elective patients.

INTRODUCTION

Gallbladder cancer (GBC) is a rare malignancy and constitutes 0.6%–1.5% of all cases after cholecystectomy, but it remains the most common cancer of the biliary tract.[12] The 5-year survival rates for all stages of GBC range from 5% to 20%, so it is considered to be an aggressive and highly lethal disease.[34] GBC is suspected preoperatively in only 30% of patients. The other 70% are discovered incidentally by pathological examinations during or after cholecystectomy for benign diseases and termed as incidental GBC.[56]

The only chance for a complete cure of GBC is by surgical resection.[7] It has been traditionally recommended that patients undergo laparotomy if they are suspected of having GBC pre-operatively.[78] Using the American Joint Committee on Cancer staging system, simple cholecystectomy (SC) alone is considered definitive treatment if the histological T-stage is Tis or T1a.[910] Whereas, tumours greater than stage T1b should be treated by extended cholecystectomy (EC), which including partial hepatic resection with or without lymphadenectomy and bile duct resection.[11]

Laparoscopic cholecystectomy (LC) has now replaced conventional open cholecystectomy for benign gallbladder disease, and hence many GBCs are diagnosed incidentally during or after LC.[5] However, the role of laparoscopic treatment for GBC has long been contraindicated. The most important reason for this contraindication was a higher incidence of wound metastasis after laparoscopic surgery.[12] However, recent studies suggested that LC has no adverse effects compared to open approach.[13] Hence, the doubt remains whether the initial laparoscopic surgery leads to a worsening of the prognosis, one objective of this study is to find out the answer of this question.

The development of new instruments and advanced surgical techniques has resulted in the more widespread use of laparoscopic surgery.[1415] Recently, laparoscopic EC (LEC) has been shown to be feasible at specialised expert centres on elective patients.[16] Considering few GBC cases are available and randomised trials are difficult to conduct, this study also conducted a pooled systematic analysis to evaluate the efficacy of laparoscopic and open EC (OEC) for GBC.

METHODS

Search strategy and study selection

A systematic review of the literature was performed. Articles published up to August 2016 were identified by searching abstracts in Medline and Cochrane Library, using the keywords: Laparoscopic; gallbladder; cancer or carcinoma. The references from the included studies were also searched to identify additional studies. Two researchers independently searched for articles and compared their results. Any discrepancies were resolved by consultation with the corresponding author.

Inclusion and exclusion criteria

To be included in this analysis, studies were required to meet the following criteria: (i) the study design must be that of a comparative trial evaluating laparoscopic and open treatment of GBC; (ii) at least one outcome should be compared; (iii) the study should be a human study and written in English.

Studies were excluded from the analysis for the following reasons: (i) unpublished data, data published in an abstract form only or non-full-length articles; (ii) failure to describe the surgical methodology; (iii) only the most recent publications were included when the selected articles included the same or overlapping data in multiple publications.

Data extraction and outcome measures

Two authors independently extracted and confirmed the data and entered them into an electronic data collection form. Differences of opinion were resolved by consensus that included the corresponding author. The following data were collected: The time period, country and design of study; the procedure type of surgery; the time of follow-up; the number of GBC patients who underwent laparoscopic and open surgery; the gender and age of patients; the number of patients by T classification; the number of patients who underwent additional operation.

The primary outcome measures were the 5-year survival rate and overall recurrence rate. Secondary outcome measures included scar recurrence, intra-operative outcomes (operative time and blood loss), and post-operative outcomes (complication rate and hospital stay). The recurrence of disease was defined as any recurrence of cancer: Distant metastasis, widespread or local peritoneal seeding, or scar recurrence. The scar recurrence was defined as a suspicious mass or nodule specially described on physical examination at an incision or port site at any time in the post-operative follow-up period.

Statistical analysis

If appropriate comparisons were available, meta-analysis was conducted. Otherwise, a descriptive review of the identified evidence was carried out. The odds ratio (OR) with 95% confidence intervals (CIs) was calculated for dichotomous data and the mean difference with 95% CIs for continuous data. Heterogeneity was described with the Chi-squared test. The value of P < 0.05 was considered to indicate a difference of statistical significance. The I2 statistic was used to measure the quantity of heterogeneity, with values >50% considered to indicate significant heterogeneity. A random-effects model was used if significant heterogeneity existed, and otherwise a fixed-effects model was adopted. All statistical analyses were performed using the statistical package RevMan (Review Manager [RevMan] [Computer program]. Version 5.3. The Nordic Cochrane Centre, The Cochrane Collaboration, 2014, Copenhagen, Denmark).

The majority of the included studies in this meta-analysis enrolled a small number of patients. This meant that when an outcome was measured, there were perhaps no events occurring. It was recommended that in such situations one event was inserted into the data extraction tables to avoid division by a zero denominator. This effectively avoided eliminating small studies from consideration.[17]

RESULTS

Baseline characteristics

Study selection and search strategy are outlined in Figure 1. A total of 12 studies were included in this review.[181920212223242526272829] There were no randomised studies and all studies were retrospective in nature. Detailed information about included studies is summarised in Table 1.

Figure 1

Flow diagram for study selection process

Table 1

Characteristics of included studies

A total of 1217 patients with GBC who underwent surgical treatment were chosen for this analysis. Seven hundred and seventy patients were in laparoscopic group, of which 730 patients underwent laparoscopic SC (LSC) and 40 patients underwent LEC. Four hundred and forty-seven patients were in open group, of which 387 patients underwent open SC (OSC) and 60 patients underwent OEC. Detailed information about these patients is shown in Table 2.

Table 2

Characteristics of patients in the included studies (laparoscopic vs. open)

Five-year survival rate

The 5-year survival rate was reported in ten of the 12 studies (1117 patients), and all compared LSC versus OSC. There was no significant heterogeneity among these studies (χ2 = 6.68, df = 9 [P = 0.67]; I2 = 0%). Using a fixed-effects model, the 5-year survival rate was significant higher in laparoscopic group than open group (353/730, 48.4% vs. 149/387, 38.5%; OR, 1.63; 95% CI, 1.22–2.19; P = 0.001) [Figure 2].

Figure 2

Meta-analysis of 5-year survival rate

Recurrence rate

Outcome measures reported in the included studies were summarized in Table 3. It was reported in ten of the 12 studies (1020 patients), of which eight studies compared LSC versus OSC and two studies compared LEC versus OEC. Thus, a subgroup analysis according to the different procedure of surgery (SC or EC) was performed. There was no significant heterogeneity among these studies (χ2 = 10.20, df = 9 [P = 0.33]; I2 = 12%), so a fixed-effects model was used. For the subgroup of SC, there was no significant difference in the rate of recurrence between the laparoscopic group and open group (282/591, 47.7% vs. 157/329, 47.7%; OR, 0.90; 95% CI, 0.67–1.20; P = 0.47). For the subgroup of EC, there was also no significant difference between two groups (1/40, 2.5% vs. 7/60, 11.7%; OR, 0.24; 95% CI, 0.04–1.35; P = 0.10). For total studies, although the recurrence rate was lower in laparoscopic group than open group, it had no significant difference (283/631, 44.8% vs. 164/389, 42.2%; OR, 0.86; 95% CI, 0.64–1.14; P = 0.29) [Figure 3].

Table 3

Outcome measures of the included studies (laparoscopic vs. open)

Figure 3

Meta-analysis of recurrence rate

Scar recurrence rate

The scar recurrence rate was reported in eight of the 12 studies (965 patients), and all compared LSC versus OSC. There was no significant heterogeneity amongst these studies (χ2 = 2.87, df = 7 [P = 0.90]; I2 = 0%). Using a fixed-effects model, the scar recurrence rate was significant higher in laparoscopic group than open group (44/616, 7.1% vs. 14/349, 4.0%; OR, 2.10; 95% CI, 1.11–3.96; P = 0.02) [Figure 4].

Figure 4

Meta-analysis of scar recurrence

Intra-opertive outcomes

The operative time was only reported in two of the 12 studies (100 patients), and all compared LEC versus OEC. One study reported that the operative time in laparoscopic group was significantly longer than open group (P = 0.02), but another study did not detect a significant difference (P = 0.76). Due to distinct presentation types of data, meta-analysis could not be performed.

The intraoperative blood loss was also reported in two of the 12 studies (100 patients), and all compared LEC versus OEC. Both studies reported that the intraoperative blood loss in laparoscopic group was significantly less than open group (P = 0.03 and P = 0.01, respectively). Due to distinct presentation types of data, meta-analysis could not be performed.

Post-operative outcomes

The complication rate was reported in two of the 12 studies (100 patients), and all compared LEC versus OEC. There was no significant heterogeneity amongst these studies (χ2 = 0.52, df = 1 [P = 0.47]; I2 = 0%), thus a fixed-effects model was used. Although the complication rate was lower in laparoscopic group than open group, it had no significant difference (4/40, 10.0% vs. 11/60, 18.3%; OR, 0.51; 95% CI, 0.15–1.73; P = 0.28) [Figure 5].

Figure 5

Meta-analysis of complication rate

The post-operative hospital stay was also reported in two of the 12 studies (100 patients). One study reported that the post-operative hospital stay in laparoscopic group was significantly shorter than open group (P = 0.01), but another study did not detect a significant difference (P = 0.11). Due to distinct presentation types of data, meta-analysis could not be performed.

DISCUSSION

Since the late 1980s, LC has been a widely accepted method for treating benign gallbladder disease.[30] However, there is controversy concerning the appropriate use of laparoscopic surgery for the treatment of GBC.[12] Since the first description of scar recurrence in 1991, it has been thought that laparoscopic surgery worsens the prognosis of GBC.[31] However, this meta-analysis showed that laparoscopic treatment for GBC had an even higher 5-year survival rate than open treatment. Although a possible explanation might be that laparoscopy was more often used to treat GBC with earlier tumour stages, the evidence from this review demonstrated that initial laparoscopic treatment did not have a measurable influence on the course of GBC.

According to previous reports, the major concern about the use of laparoscopic surgery for patients with GBC is metastatic wound implants arising from trocar holes.[13] This meta-analysis indeed detected a higher incidence of scar recurrence in laparoscopic group than the open group. However, the overall recurrence rate between two groups had no significant difference. A retrieval bag was advised by several studies in cases with perforation of gallbladder and contributed to prevent stone spillage, scar recurrence and intraperitoneal dissemination. Hence, by means of adherence to oncologic principles and use of retrieval bags, scar recurrence might not be a concern when applying laparoscopic surgery on patients with GBC.[1332]

The advances in instrumentation and technical improvements have resulted in the more widespread use of laparoscopic surgery to treat most cancers of digestive system, including colon, stomach, liver and even pancres. It has been demonstrated to show similar oncological outcomes with open surgery, and provide additonal benefits of minimally invasive surgery.[15323334] Recently, LEC has been performed at several specialised expert centres. These centres have reported safe and feasible outcome data for T1b, T2 and even T3 tumours.[1635] In this analysis, two retrospective studies comparing LEC versus OEC were included. The results showed that there was no significant difference in regard to recurrence rate and complication rate between the two surgical types, but laparoscopic surgery was associated with less intraoperative blood loss and shorter post-operative hospital stay. So, based on the evidence provided by this review, it was concluded that LEC could be performed in specialised expert centres on elective patients.

This systematic review and meta-analysis had a number of limitations. First, carrying out a randomised controlled trial (RCT) that compares laparoscopic and open treatment for GBC was very difficult, and all studies included were retrospective. Second, most published studies on GBC were based on a single-centre experience with a relatively small number of patients. Third, the variable patient selections, laparoscopic and open procedures, and different outcome measures might be attributable to the heterogeneity of included studies. Forth, the follow-up period was limited to access long-term survival rate of different surgical types. Therefore, a large-sample, well-conducted, multicentre RCT including long-term follow-up will be required to further confirm the results of the present analysis.

CONCLUSION

The evidence from this analysis did not show that LSC leads to a worsen prognosis when applied on patients with GBC. Moreover, LEC could be performed in specialised expert centres on elective patients.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.