Laparoscopic versus open surgery in treating patients with gallbladder cancer: a systematic review and meta-analysis

Introduction

Gallbladder cancer (GBC) is rare, as it accounts for 1.2% of all cancer cases and 1.7% of all cancer deaths (1). The majority of GBC patients are diagnosed at advanced stages, and the prognosis is unsatisfactory, with a 5-year survival rate less than 20% worldwide (2). Factors that benefit the prognosis of GBC patients include early diagnosis and proper treatment.

With the advancement of surgical techniques and instruments, minimally invasive surgeries such as laparoscopic surgery (LS) to treat gastrointestinal malignancies have gained widespread popularity (3-5), and can greatly reduce morbidity by reducing blood loss and shortening length of hospital stay (6-8). However, the security of LS in the management of GBC has aroused special concerns. Some clinical studies have compared the safety and efficacy of LS with open surgery (OS), yet no consensus was reached thus far. For example, a meta-analysis of 18 studies conducted by Lv et al. (9) supported the superiority of LS in postoperative rehabilitation. Similarly, another meta-analysis of 14 studies by Nakanishi et al. (10) showed a trend favoring LS as a possible alternative treatment option vis-à-vis OS in the management of GBC, and importantly they found that survival outcomes were improved in patients at T2 and T3 stages who received LS, differing from the nonsignificant observations by Lv et al. (9). Therefore, whether LS can be recommended as a routine surgical option for GBC still remains an open question, calling for further evaluation in a comprehensive manner.

To yield more information and provide evidence basis for future investigations, this systematic review and meta-analysis aimed to comprehensively compare the safety and efficacy of LS versus OS in the management of GBC patients. The research has been reported in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting checklist (available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-22-597/rc) and AMSTAR (Assessing the Methodological Quality of Systematic Reviews) guidelines (available at https://cdn.amegroups.cn/static/public/hbsn-22-597-1.pdf) (11).

Methods

Search strategy

The PubMed, EMBASE (Excerpt Medica Database), and Web of Science were searched from inception until July 18, 2022. Search terms are shown in the supplementary materials (Appendix 1). Two authors (D.L. and L.X.) independently completed literature search, and all retrieved articles were combined with manual removal of duplicates.

Eligibility criteria

Studies eligible for inclusion in this systematic review and meta-analysis should simultaneously fulfill the following criteria: (I) comparative studies evaluating LS vis-à-vis OS in the treatment of GBC; (II) studies involving human beings and written in the English language; (III) outcomes focusing on survival or intraoperative or postoperative outcomes.

Studies were excluded for the following reasons: (I) non-comparative studies such as abstracts, letters, reviews, case reports, and laboratory studies; (II) studies involving robotic surgeries.

Study identification

Initially, titles and abstracts were reviewed for selection, and in the case of uncertainty full texts and supplementary files (Appendix 1) if available were reviewed. The identification process was performed by two authors (D.L. and L.X.) independently, and disagreement was resolved by discussion or consulting with a third author (Z.Y.).

Data extraction and quality assessment

Data were extracted from each eligible study independently by two authors (D.L. and L.X.) using a standardized data form, and discrepancies were adjudicated by a third author (Z.Y.). Extracted data included first author’s name, year of publication, country where study was conducted, ethnicity, study design, surgery procedure type, sample number of incidental GBC diagnoses, sources of patients, sample size in LS and OS, 1-, 2-, 3-, and 5-year disease-free rates, 1-, 2-, 3-, and 5-year survival rates for each tumor stage, operation time, intraoperative blood loss, transfusion rate, number of harvested lymph nodes (LNs), R0 resection rate, days of postoperative hospital stay, postoperative morbidity rate, recurrence rate, and port-site metastasis rate. The 1-, 2-, 3-, and 5-year survival rates for each tumor stage were extracted and calculated from either reported literature values or raw data. When survival rates could not be directly obtained from the context, the Kaplan-Meier (KM) curves were digitized using the Engauge Digitizer software (version 4.1) and literately computed to generate individual patient data and survival rates.

The quality of each study was independently evaluated by two authors (D.L. and L.X.) using the Newcastle-Ottawa Scale. Quality assessment scores are shown in Table S1.

Statistical analyses

The STATA software version 14.1 (StataCorp, College Station, TX, USA) was used for this systematic review and meta-analysis.

Odds ratio (OR) and 95% confidence interval (CI) were calculated to assess discrete outcomes. Weighted mean difference (WMD) and 95% CI were calculated to assess continuous outcomes.

The inconsistency index (I²) was employed to quantify the magnitude of statistical heterogeneity, and it represents the percentage of observed variability between studies that is due to heterogeneity instead of chance. It is widely accepted that heterogeneity is deemed statistical significance if the I² exceeds 50%, and higher I² denotes stronger evidence of heterogeneity (12). In this systematic review and meta-analysis, effect-size estimates were derived under the random-effects model because of the assumption of clinical and methodological heterogeneity across studies, which can often lead to statistical heterogeneity. What’s more, in case of no statistical heterogeneity, fixed-effects and random-effects models yield nearly identical estimates, and in the presence of statistical heterogeneity, random-effects model is preferred (13). Clinical and methodological heterogeneity across studies was assessed by means of subgroup analyses.

Cumulative analyses were conducted to assess the impact of the first publication on subsequent publications and the evolution of the accumulating estimates over time. Sensitivity analyses were conducted to assess the impact of any individual publications on overall effect-size estimates by omitting one study at a time.

Publication bias refers to the reduced likelihood of studies’ results being published when they are near the null, lacking of statistical significance, or otherwise of little interest (14). To appraise the presence of publication bias, Begg’s funnel plots were displayed for visual inspection of symmetry. In addition, Begg’s tests and Egger’s tests were used to statistically assess funnel asymmetry and quantify the probability of publication bias, with significance set at a level of 10%. In addition, the Duval and Tweedie nonparametric “trim and fill” method was used to take theoretically missing studies into consideration and generate theoretically “unbiased” effect-size estimates.

Results

Qualified studies

Initially, a total of 7,972 potentially eligible articles published in the English language were retrieved after scanning predefined public databases, and of them, 27 independent studies involving 2,868 participants were synthesized in this systematic review and meta-analysis. The selection process annexed with concrete reasons for article exclusion is shown in Figure S1.

Study characteristics

All qualified studies were retrospective in design. Of 27 studies analyzed, 4 studies enrolled patients from multicenters (15-18), and 23 studies are single center studies (7,19-40). Twenty-two studies reported overall survival, 10 T1-staged survival, 12 T2-staged survival, 7 T3-staged survival, and 9 disease-free survival. Intraoperative and postoperative data were extracted, including operative time, intraoperative blood loss, postoperative hospital stay, postoperative morbidity, R0 resection rate, transfusion rate, number of harvested LNs, overall recurrence, and port-site metastasis.

Baseline characteristics

Table 1 shows the baseline characteristics of qualified studies in this systematic review and meta-analysis. All studies were published from the year 2000 to 2022. The total sample size ranged from 16 to 834. Of 2,868 patients, 1,442 and 1,426 patients underwent LS and OS, respectively.

Survival outcomes

As for disease-free survival, no significant difference existed at 1-year (OR: 1.310), 2-year (OR: 1.266), 3-year (OR: 1.377), and 5-year (OR: 1.393) (all P>0.01) between patients undergoing LS and OS.

Regarding overall survival, a higher survival rate was noted in patients undergoing LS than with OS at 2-year (OR: 1.524, P<0.01). Contrastingly, 1-year (OR: 1.193), 3-year (OR: 1.352), and 5-year (OR: 1.284) (all P>0.01) survival rates were similar between patients undergoing LS and OS.

At T1 tumor stage, pooled survival rate showed no statistical significance at 1-year (OR: 0.783), 2-year (OR: 0.785), 3-year (OR: 0.747), and 5-year (OR: 0.689) (all P>0.01). At T2 tumor stage, pooled survival rate was higher in patients undergoing LS than with OS in 1-year (OR: 1.799), and 2-year (OR: 2.026) (both P<0.01). By contrast, 3-year (OR: 1.013), and 5-year (OR: 1.070) (both P>0.01) survival rates were comparable between patients undergoing LS and OS at T2 tumor stage.

Likewise, at T3 tumor stage, 1-year (OR: 2.669) and 2-year (OR: 2.300) (both P<0.001) survival rates were higher in patients undergoing LS than OS. However, 3-year (OR: 2.116) and 5-year (OR: 2.517) (both P>0.01) survival rates were similar between the two groups (Table 2). Forest plots of survival outcomes are shown in online figure (Fig. S2; available at https://cdn.amegroups.cn/static/public/hbsn-22-597-2.doc).

Intraoperative outcomes

Comparisons of intraoperative outcomes between patients undergoing LS and OS are shown in Table 2 and forest plots are shown in online figure (Fig. S2; available at https://cdn.amegroups.cn/static/public/hbsn-22-597-2.doc).

There were no significant differences between patients undergoing LS and OS in operation time (WMD: 5.160), R0 resection rate (OR: 1.862), and transfusion rate (OR: 1.390) (all P>0.01). Patients undergoing LS had less intraoperative lower blood loss (WMD: −117.194) and a smaller number of harvested LNs (WMD: −1.023) than those undergoing OS (both P<0.01).

Postoperative outcomes

Comparisons of postoperative outcomes between patients undergoing LS and OS are presented in Table 2 and forest plots are shown in online figure (Fig. S2; available at https://cdn.amegroups.cn/static/public/hbsn-22-597-2.doc).

Patients undergoing LS had shorter postoperative hospital stay (WMD: −3.555) and lower postoperative morbidity (OR: 0.596) than those undergoing OS (both P<0.01). No significance was observed between patients undergoing LS and OS in recurrence (OR: 1.042) and port-site metastasis (PSM) (OR: 1.597) (both P>0.01).

Subgroup analyses

Considering significant heterogeneity in overall comparisons, there is a need to explore possible causes. Subgroup analyses were conducted according to ethnicity, proportion of incidental GBC, proportion of Tis & T1 & T2, sample size, publication year, and follow-up period to compare differences in survival, intraoperative, and postoperative outcomes between patients undergoing LS and OS (Tables 3-6). The corresponding forest plots are shown in online figure (Fig. S3; https://cdn.amegroups.cn/static/public/hbsn-22-597-2.doc). Considering the limited number of studies in some subgroups, analyses were conducted only on items involving 10 or more independent studies.

By ethnicity, survival outcomes (T2 survival and overall survival) were significantly improved in patients of European origin who underwent LS relative to OS, and contrastingly improvement in intraoperative and postoperative outcomes was seen in patients of Asian origin, except for recurrence rate and PSM rate. By proportion of incidental GBC, there was significant improvement in survival outcomes in studies exclusively involving incidental GBC, as well as in postoperative hospital stay, and in studies involving both incidental and non-incidental GBC, significance was observed for intraoperative blood loss and number of harvested LNs. By total sample size, improvement in survival outcomes was seen in studies with total sample sizes ≥60, as well as in intraoperative and postoperative outcomes, indicating the robustness of our observations.

By publication year, statistical significance was seen for survival outcomes in studies published before 2019, yet the magnitude of effect-sizes was comparable with that of studies published after 2019. For intraoperative and postoperative outcomes, effect-sizes were statistically significant in studies published both before and after 2019. By follow-up period, only significance was seen for intraoperative and postoperative outcomes in studies irrespective of periods, and effect-size magnitude was stronger in studies with follow-up period ≥36 months.

Cumulative analyses

In cumulative analyses, there was no hint of significant impact from the first publication on subsequent publications for survival, intraoperative and postoperative outcomes (Fig. S4; available at https://cdn.amegroups.cn/static/public/hbsn-22-597-2.doc).

Sensitivity analyses

Sensitive analyses were conducted by removing each individual study to evaluate whether any single study had a significant impact on pooled estimates, and no significance was detected for most outcomes except intraoperative blood loss, postoperative hospital stay, and operation time (Fig. S5; available at https://cdn.amegroups.cn/static/public/hbsn-22-597-2.doc).

It is worth noting that as for T2 survival outcomes, exclusion of the study by Goetze and colleagues (18) involving merely incidental GBC patients exerted a large impact on pooled estimates, and considering the overlapping CIs this impact was not significant.

Publication bias

The Begg’s tests and Egger’s tests were used to evaluate potential publication (Table 2). Postoperative morbidity (Egger’s test P=0.035) and survival of T2 stage at 1-year (Egger’s test P=0.026) had a significantly high probability of publication bias. The effect-size estimates for survival of T2 stage at 1^st year still remained statistically significant (P<0.001) after taking 5 theoretically missing studies into consideration. By contrast, the effect-size estimates for postoperative morbidity were nonsignificant (P=0.061) after additionally adding 3 theoretically missing studies (Fig. S6; available at https://cdn.amegroups.cn/static/public/hbsn-22-597-2.doc).

Discussion

The aim of this systematic review and meta-analysis was to comprehensively compare the safety and efficacy of LS versus OS in the treatment of GBC patients. Our major findings indicated that LS was generally superior to OS for GBC in terms of overall 2-year survival, 1- and 2-year survival at T2 and T3 stages. Moreover, LS was found to be associated with less intraoperative blood loss, less postoperative morbidity, higher R0 resection rate, and shorter postoperative hospital stay than OS. To the best of our knowledge, this is thus far the largest systematic review and meta-analysis that has comprehensively compared LS with OS from safety and efficacy aspects in treating GBC in the medical literature.

In routine clinical practice, LS is not generally accepted as a priority option for GBC. With the development of laparoscopic technique, a growing number of studies have adopted LS in the management of GBC. Of all patients diagnosed with GBC, about 60–80% were incidental (41), and patients with incidental GBC had a good prognosis relative to non-incidental GBC cases (42-44). It is widely accepted that for incidental GBC, radical surgery involving resection of gallbladder liver beds and regional lymph nodes was the most popular choice to achieve R0 margins and proper staging (45). Vega et al. reported that prior nononcologic surgery for incidental GBC can affect survival and lead to a worse prognosis (46), which was confirmed in this study after restricting analysis to patients with incidental GBC, showing that LS was associated with better overall survival and T2-stage survival than OS. However, we failed to support the superiority of LS over OS for early T-stage GBC, which led us to speculate that this superiority was not entirely attributable to early T-stage of incidental GBC. Nevertheless, we cannot exclude the possibility that selection of LS for patients with incidental GBC in good general conditions accounts for the advantages of LS in our overall analyses, and we agree that further validations in large-scale, well-designed comparative studies are required.

There is evidence that N status is one of the strongest prognostic determinants in patients undergoing operations for GBC (47), and regional lymphadenectomy can improve survival outcomes (48). As recommended by Dou et al. (49), relatively-early GBC cases (Tis-T1a or T1b-T2) should be selected in the beginning to accumulate operational experience and standardize surgical process, and gradually transit to advanced stage (T3) GBC cases. In other words, surgeons carrying out LS for GBC should have extensive experience in laparoscopic liver resection, bilioenterostomy, and lymph node dissection, which form an important basis for the safe and smooth implementation of LS. In our overall analyses, LS was found to be associated with less harvested LNs, and in the subgroup involving GBC patients at Tis & T1 & T2, LS had significantly fewer harvested LNs than OS, consistent with the findings by Ong et al. in a Swiss nationwide population-based analysis (50). The reasons behind the small number of harvested LNs might be due to lack of awareness that LN removal is a crucial component of oncologic resections, technical inability to perform lymphadenectomy, and learning curve of surgeons. For instance, it is suggested that learning curve of pure LS was about seven cases if surgeons had sufficient experience in laparoscopic hepatectomy (22). Also, minimally invasive technology can perform equally well in terms of the number of harvesting nodes (51,52). Taking this information together, it can be speculated that these findings might, at least in part, be influenced by the beginning of the learning curve. As recommended by expert consensus statement (53), at least 6 LNs should be resected in GBC radical surgery. Considering the fact that 3 of 15 studies reporting harvested LNs had resected less than 6 LNs, we here suggest the implementation of LS at high-volume centers with specialized experience. Therefore, the superiority of LS over OS in better survival and lower LNs observed in this systematic review and meta-analysis might be, at least in part, explained by the preference of LS in GBC patients at earlier stages, with less LN metastasis, and better general conditions.

Tumor recurrence is another important factor impacting postoperative survival of GBC. However, in this systematic review and meta-analysis, we failed to detect any hints of significance in recurrence and PSM rates between patients undergoing LS and OS. Recently, growing concerns have been expressed over PSM, an indicator of poor prognosis (54), when applying LS for the management of GBC. Some experts in this field claimed that PSM rate was comparable between LS and OS pending improved recognition of GBC and implementation of plastic bags to remove resected gallbladder (3). In support of this claim, 11 of 16 eligible studies in this systematic review and meta-analysis reported no occurrence of PSM. Actually in surgical practice, PSM cannot be totally avoided, and it is essential to enhance surgical skills and enrich practical experience of LS to avoid PSM occurrence to the outmost extent.

Finally, several limitations should be addressed for this systematic review and meta-analysis. Firstly, this study is based on retrospective cohorts, and recall bias cannot be fully ruled out. Secondly, because only published studies written in the English were synthesized and the “grey” literature was not covered, publication bias might be possible. As reflected by funnel plots and statistical tests, the possibility of publication bias was high for survival of T2 stage at 1-year and postoperative morbidity, likely due to lack of statistical power from limited numbers or small sizes of studies meta-analyzed. Thirdly, although a wide panel of subgroup analyses were conducted to seek potential sources of between-study heterogeneity, some unaccounted residual confounders such as surgical procedures were not taken into consideration. Fourthly, as a meta-analysis cannot replace studies from high-volume centers involving large sample sizes, we agree that more well-designed studies are required to derive a more precise estimate of clinically important outcomes when comparing LS with OS in the management of GBC patients.

Conclusions

Taken together, our findings indicated that LS statistically had better 2-year survival rates, less intraoperative bleeding, shorter hospitalization times, and lower rates of complications than OS. However, due to the impact of incidental GBC, unaccounted heterogeneity, publication bias, and lack of high-quality randomized controlled trials, the superiority of LS over OS remains a subject of debate. Moreover, uncertainties such as lymph node dissection and port-site metastasis have not been fully understood, and the safety of LS still remains an open question. More recently, laparoscopic radical surgery for GBC has gained increasing popularity at major hepatobiliary centers. We believe that the confusion on different treatment options for GBC will be gradually cleared up with the accruing evidence to outline the pros and cons of each option.

Acknowledgments

Funding: This work was supported by the National Key Clinical Specialty Construction Project of General Surgery Department (Hepatobiliary Surgery Department) (No. 2021-QTL-004).

Footnote

Reporting Checklist: The authors have completed the PRISMA reporting checklist. Available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-22-597/rc

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-22-597/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study has been registered in PROSPERO and the unique identifying number or registration ID is CRD42022369697.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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