Central hepatectomy versus major hepatectomy for patients with centrally located hepatocellular carcinoma; a systematic review and meta-analysis

doi:10.21203/rs.3.rs-1957571/v1

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Central hepatectomy versus major hepatectomy for patients with centrally located hepatocellular carcinoma; a systematic review and meta-analysis

https://doi.org/10.21203/rs.3.rs-1957571/v1

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published 05 Jan, 2023

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Background and Aim: For those with a centrally located HCC, the two types of liver sectionectomy that can be performed are extended hepatectomy (EH) and central hepatectomy (CH). The aim of this meta-analysis was to compare the short- and long-term outcomes between patients treated with CH and patients treated with EH for those with centrally located HCC.

Method: We searched PubMed, Scopus, Web of Science, Cochrane library for eligible studies from inception to 1 April 2022 and a systematic review and meta-analysis were done to compare the outcomes between the two groups.

Results: we included 9 studies with total of 1674 patients in this study. The pooled results in this meta-analysis showed equal long-term overall survival, Disease free survival, recurrence and mortality between the two groups (5-year OS, RR = 1.14, 95% CI = 0.96-1.35, P = 0.12; I2 = 56%), (5-year DFS, RR = 0.81, 95% CI = 0.61-1.08, P = 0.15; I2 = 60%), (Recurrence, RR =1.04, 95% CI = 0.94-1.15, P = 0.45; I2 = 27%), and (Mortality, RR =0.55, 95% CI = 0.26-1.15, P = 0.11; I2 = 0 %). In addition to that, no significant difference could be detected in the overall incidence of complications between the two groups (Complications, RR =0.94, 95% CI = 0.76-1.16, P = 0.57; I2 = 0 %).However, CH is associated with a remarkable increase in the rate of biliary fistula (Biliary fistula, RR =1.90, 95% CI = 1.07-3.40, P = 0.03; I2 = 0%). And Liver cell failure was higher in case of EH (LCF, RR =0.47, 95% CI = 0.30-0.76, P = 0.002; I2 = 0%). Regarding the operative details, CH is associated with longer operative time (Time of the operation, Mean difference = 0.82, 95% CI = 0.36, 1.27, P = 0.0004; I2 = 57%).

Conclusion: No significant difference in the short and long-term survival and recurrence between CH and MH for CL-HCC. However, CH is associated with greater future remnant liver volume that decreases the incidence of LCF and provides more opportunities for a repeat hepatectomy after tumor recurrence.

Hepatocellular carcinoma (HCC) is the fifth-most common cancer globally and the third-highest cause of cancer-related death exceeded only by cancers of the lung and stomach.¹ It is estimated that 782,000 new cases are diagnosed with HCC annually and 600,000 die of this tumor globally each year.² Therapeutic treatment modalities are available for patients with local disease including ablation, liver resection, and liver transplantation (LT). However, for those with respectable tumors and without underlying liver disease, liver resection offers the best treatment.³

Based on Couinaud’s segmental anatomy of the liver, centrally located HCC is defined as tumors located in the middle part of the liver (segments IV, V, or VIII ± I).⁴ For those with a centrally located HCC, the two types of liver sectionectomy that can be performed are, firstly: a major hepatectomy (MH) or an extended hepatectomy (EH) which includes a right/left hemihepatectomy or right/left trisectionectomy and secondly: a central hepatectomy (CH) which involves a left medial sectionectomy, right anterior sectionectomy, or central bisectionectomy (mesohepatectomy).

On one hand, Traditionally, Hemi- or extended hepatectomy is suggested for the treatment of CL-HCC.⁵ However, This modality includes the excision of 60–85% of liver parenchyma.^6,7 Which in turn increases the risk of postoperative liver failure and is associated with higher mortality and morbidity rates.^8,9 On the other hand, central hepatectomy allows up to 35% parenchymal sparing compared to EH.¹⁰ However, CH has been associated with biliary fistula¹¹, significant blood loss^6,12, a longer operative time^6,13. This could be explained by the presence of technical challenges related to the presence of two significant parenchymal transection planes in proximity to the hilar bifurcation.

The aim of this meta-analysis was to compare the short- and long-term outcomes including overall survival, recurrence rate and complications between patients treated with CH and patients treated with Hemi-/extended hepatectomy for those with centrally located HCC.

Search Strategy

PubMed / MEDLINE, Scopus, Web of science, and the Cochrane Library were searched for data from inception to 1 April, 2022 with the following terms: major hepatectomy and Mesohepatectomy or central Hepatectomy and hepatocellular carcinoma. More searches by Google Scholar have been used to supplement the search with the sites mentioned above. according to the eligibility process. Abstract-based eligibility studies were obtained, and the manuscripts were fully reviewed. Report bibliographies that meet the eligibility criteria were reviewed for further studies. All studies were reviewed and evaluated by two authors (Gadallah, E. A. & Elkomos, B. E.).

Inclusion and Exclusion Criteria

The eligible studies included the following: (1) randomized controlled trials and prospective or retrospective cohort studies; (2) target population were patients with hepatocellular carcinoma; (3) studies designed to compare central hepatectomy versus extended hepatectomy for hepatocellular carcinoma; (4) studies providing a sufﬁcient description of the methods and baseline characteristics, and (5) the main outcomes were patient overall survival, disease free survival for both central and major hepatectomy. The following types of studies were not included in our study: (1) unrelated or in vitro studies; (2) reviews, case reports and case series; (3) patient diagnosed with liver cancers other than hepatocellular carcinoma: (3) studies missing a comparison group.

Outcomes of Interest

We assessed 6 primary outcomes for central and extended hepatectomy for hepatocellular carcinoma in this meta-analysis, including overall survival (1,2,3,4,5-year OS), disease free survival (1,2,3,4,5-year DFS), recurrence, early post-operative mortality, complications (liver cell failure, biliary fistula, wound infection and ascites), operative details (the time of the operation, the blood loss during the operation, blood transfusion and hospital stay after operation).

Data Extraction

We extracted data on study characteristics (author, year of publication, country of operation, type of study and sample size), patient characteristics (age, sex, child score, virology and cirrhosis), tumor biology (tumor size, tumor number and vascular invasion), operative details (the time of the operation, the blood loss during the operation, blood transfusion, hospital stay after operation and resection margin), Patients outcome (overall survival, disease free survival, recurrence and mortality) and complications (overall incidence of complications, liver cell failure, biliary fistula and wound infection). The data were extracted by 2 investigators (Gadallah, E. A. & Elkomos, B. E.) independently.

Statistical Analysis

The meta-analysis was performed according to Cochrane Handbook for Systematic Reviews of Interventions,¹⁴which is recommended by the Cochrane Collaboration. For all the results included, the pooled risk ratios (RRs) and their corresponding 95% conﬁdence intervals (CIs) were calculated with fixed effects models. However, if there was moderate or considerable heterogeneity (I²> 40), random effects models were used to solve the heterogeneity between studies. All calculations for the current meta-analysis were performed with Review Manager 5.4 for Windows (Cochrane Collaboration, Oxford, United Kingdom).

Assessment of Publication Bias and Heterogeneity

Funnel plots were generated so that we could visually inspect for publication bias. The statistical methods for detecting funnel plot asymmetry were the Begg Mazumdar rank correlation test and the Egger regression asymmetry test. Statistical heterogeneity was assessed with forest plots and the inconsistency statistic (I2). An I2 value of 40% or less corresponded to low heterogeneity. Statistical signiﬁcance was considered at P < 0.05.

Characteristics and Quality Assessment of Eligible Studies

As shown in the flow diagram (Fig. 1),1186 articles were revealed using a combination of the following words: major hepatectomy and Mesohepatectomy or central Hepatectomy and hepatocellular carcinoma. After careful selection based on our eligibility criteria, 9 studies with 1674 patients were included in the meta-analysis. All the included studies were cohort studies. The studies were conducted in four different countries (China, Taiwan, Japan and Mongolia).

Patients characteristics (age, sex, child score, virology and cirrhosis), tumor biology (tumor size, tumor number and vascular invasion) were comparable between the two group in all studies. (Table 1)

Overall survival

8 studies (1634 participants) assessed 1-year OS, 7 studies (1530) reported 3-year OS and 7 studies (1565) calculated 5 year-OS. The pooled results from these studies showed equal overall survival for those who underwent central hepatectomy and extended hepatectomy as follow (1-year OS, RR = 1.00, 95% CI = 0.96–1.04, P = 0.92; I2 = 16%), (3-year OS, RR = 1.13, 95% CI = 0.97–1.33, P = 0.12; I2 = 71%) and (5-year OS, RR = 1.14, 95% CI = 0.96–1.35, P = 0.12; I2 = 56%). 5-year OS was 43.3% for CH and 39.8% for EH. However, the pooled results for the 2 and 4-year overall survival showed possible improvement in the overall survival for those who underwent extended hepatectomy (2-year OS, RR = 1.14, 95% CI = 1.06–1.23, P = 0.0005; I2 = 21%) and (4-year OS, RR = 1.31, 95% CI = 1.16–1.48, P < 0.0001; I2 = 8%) as shown in 6 studies (855) for 2-year OS and 5 studies (765) for 4-year OS. 4-year OS was 56.9% for CH and 47% for EH. Figure 2 summarizes 1-, 2-, 3-, 4-and 5-year OS for CH and EH recipients.

Disease free survival

8 studies (1605 participants) reported 1-year DFS, 5 studies (765 participants) assessed 2-year DFS, 7 studies (1447 participants) reported 3-year DFS, 5 studies (765 participants) calculated 4-year DFS and 7 studies (1565 participants) assessed 5-year DFS. The pooled results from these studies showed no significant difference between CH and EH. For instance, 5-year DFS was 24.4% for CH and 28.2% for EH. Figure 3 summarizes 1-, 2-, 3-, 4- and 5-year DFS for CH and EH recipients.

Recurrence

Regarding the recurrence after hepatectomy as reported by 4 studies (1081 patients), no significant difference could be detected between the groups (Recurrence, RR = 1.04, 95% CI = 0.94–1.15, P = 0.45; I2 = 27%) Fig. 4. According to the pooled results of these studies, the recurrence was 56.4% for those who underwent CH and 54.3% for those who underwent EH.

Mortality

In addition to that, as reported by 8 studies (1626), the early post-operative mortality during the first three months after surgery was nearly equal for the two modalities. It was an average of 2% for both groups. (Mortality, RR = 0.55, 95% CI = 0.26–1.15, P = 0.11; I2 = 0%) Fig. 5.

Complications

Turning to post-operative complications, no remarkable difference in the total incidence of post-operative complications in the two groups. As reported by 7 studies (1270 patients), the pooled results showed 19.9% complication rate for CH and 19.8% for EH. (Complications, RR = 0.94, 95% CI = 0.76–1.16, P = 0.57; I2 = 0%) Fig. 6.

Liver cell failure

On one hand, liver cell failure was calculated for the two groups in 6 studies (1415 participants) and its incidence was higher in EH group 5.3% in comparison to 3% in CH group. (LCF, RR = 0.47, 95% CI = 0.30–0.76, P = 0.002; I2 = 0%) Fig. 7.

Biliary fistula

On the other hand, biliary fistula was reported in 7 studies (1455 patients) and the rate was higher in CH group 5% in comparison to 2.5% for EH group. (Biliary fistula, RR = 1.90, 95% CI = 1.07–3.40, P = 0.03; I2 = 0%) Fig. 8.

Ascites

According to 4 studies (1084 participants), no significant difference could be detected in the rate of post-operative ascites in the two groups. (Ascites, RR = 1.95, 95% CI = 1.00-3.78, P = 0.05; I2 = 0%) Fig. 9.

Wound infection

Moreover, as reported by 5 studies (1282 patients), no remarkable difference in the incidence of wound infection for the two modalities. (Wound infection, RR = 0.77, 95% CI = 0.39–1.52, P = 0.44; I2 = 0%) Fig. 10.

Operative details

Time of operation

Turning to the duration of the operation, according to 4 studies (328 patients), the average time for surgery was longer in CH than in EH. (Time of the operation, Mean difference = 0.82, 95% CI = 0.36, 1.27, P = 0.0004; I2 = 57%). Figure 11

Blood loss during operation

According to three studies (280 participants), no remarkable difference could be detected in the blood loss during the operation for both methods (Blood loss, Mean difference = 40.87, 95% CI = -8.81, 90.54, P = 0.11; I2 = 13%). Figure 12

Blood transfusion

In addition to that, as reported by three of the included studies (224 participants), the average amount of blood transfusion was similar for the two groups. (Blood transfusion, Mean difference = 269.54, 95% CI = -169.28, 708.35, P = 0.78; I2 = 23%). Figure 13

Hospital stay

In addition to that, according to the pooled results from three studies (280 participants) the two groups had equal time of hospitalization. (Hospital stay, Mean difference = -2.17, 95% CI = -5.56, 1.22, P = 0.21; I2 = 83%). Figure 14

Publication Bias Assessment

There was no evidence of publication bias. The funnel plot analysis demonstrated a symmetrical appearance, and the P values were greater than 0.05 for all comparisons according to the Begg-Mazumdar test and eggers test.

Hepatocellular carcinoma (HCC) is the primary liver cancer derived from hepatocytes and accounts for 85–90% of all primary liver cancers.² Liver resection, ablation and transplantation are the curable treatment options for this tumor and according to BCLC treatment recommendations for HCC, liver resection offers the best treatment for HCC without an underlying liver disease.³ The two types of liver resection that can be performed for centrally located HCC are major hepatectomy (MH) or extended hepatectomy (EH) and central hepatectomy (CH) that was first performed by McBride and Wallace 1972 as a treatment for gall bladder cancer and intended as en bloc excision of the Couinaud’s segments 4, 5, 8 ± 1.

To begin with overall survival after hepatectomy, while some studies reported better overall survival for those who underwent central hepatectomy ^20,21, other studies said that the overall survival was equal between the two modalities^17,19. In our meta-analysis a trivial improvement could be detected in the 2- and 4- years OS for those who underwent CH. However, no significant difference could be detected in the 5-year OS between the two modalities. Moreover, the incidence of post-operative mortality and DFS were similar in the two groups.

Regarding the recurrence rate of HCC, as reported by some studies, central hepatectomy increase the chance for a future repeat resection. ^22,23 However, according to the pooled results from the included studies, no remarkable difference could be detected in the recurrence rate between the two types of liver resection. In addition to that as reported by Orimo et al ²¹. hepatectomy that was more in CH group not because liver recurrence was more common in CH group, but because the sufficient remnant liver that was preserved in CH group that could be removed after recurrence.

Our meta-analysis showed that the overall incidence of complications was comparable between the two modalities. However, on one hand, the incidence of post-operative liver cell failure was significantly higher in those who underwent major hepatectomy. This could be attributed to the fact that major hepatectomy is associated with the removal of 60–85% of liver parenchyma.^6,7 On the other hand, a higher incidence of biliary fistula was detected for those who underwent central hepatectomy.

Turning to the operative details, many studies reported that central hepatectomy is associated with greater operative blood loss and the need to operative blood transfusion^6,12 and this was explained by technical complexity, which is result from the presence of two parenchymal transection planes in proximity to the hilar bifurcation^5,15. As a result, it requires challenging handling of the right hepatic vein exposed along the right section plane, middle hepatic vein at its distal end, biliary confluence, and first- and second-order portal pedicles.

However, the pooled results showed no remarkable difference between CH and MH in terms of blood loss and blood transfusion during the operation. It is worth mentioning that the operative time was longer in case central hepatectomy.

For our knowledge it is the largest meta-analysis to compare between the two types of resection for HCC as all the studies that were comparing the outcomes between the two modalities were included. However, we have to admitted that all the included studies were cohort studies which is considered a limitation in our study because no randomized controlled trails could be found.

In conclusion, this study showed no significant difference in the short and long term survival and recurrence between CH and MH for CL-HCC. However, CH is associated with greater future remnant liver volume that decrease the incidence of LCF and provides more opportunities for a repeat hepatectomy after tumor recurrence.

CONFLICT OF INTERESTs:

The authors declare no conflict of interests

Authors' contributions:

- Edward Atef Gadallah: Data gathering and data extraction.

-Beshoy Effat Elkomos: Data gathering, data extraction.figures 1 and all tables

- Ahmed Khalil: Done the statistical analysis of the meta-analysis all figures except No1

- Amr Abdelaal: writing the manuscript.

- Fawzy Salah fawzy: helped writing the manuscript.

Acknowledgements:

This research would not have been possible without the exceptional support and effort of our supervisors, Prof. Dr Amr Abdelaal. Prof Dr Ahmed Khalil, Dr Fawzi Salah.

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Table 1 is available in the Supplementary Files section

No competing interests reported.

Table1basicdataoftheincludedstudies..pdf

Download PDF

Journal Publication

published 05 Jan, 2023

Read the published version in BMC Surgery →

First submitted to journal
12 Aug, 2022

You are reading this latest preprint version

Central hepatectomy versus major hepatectomy for patients with centrally located hepatocellular carcinoma; a systematic review and meta-analysis

Status:

Journal Publication

Version 1

Abstract

Figures

Introduction

Patients And Methods

Results

Characteristics and Quality Assessment of Eligible Studies

Overall survival

Disease free survival

Recurrence

Mortality

Complications

Liver cell failure

Biliary fistula

Ascites

Wound infection

Operative details

Time of operation

Blood loss during operation

Blood transfusion

Hospital stay

Publication Bias Assessment

Discussion

Declarations

References

Table

Additional Declarations

Supplementary Files

Status:

Journal Publication

Version 1