Objective

To evaluate the efficacy and safety of laparoscopic major hepatectomy for hepatocellular carcinoma patients.

Summary of background data

Despite the popularity of laparoscopic hepatectomy, it is still in need of further evidence to assess its safety and efficacy for the treatment of hepatocellular carcinoma.

Methods

From 2008 to 2017, 149 patients (laparoscopic right hepatectomy [LRH], 28 patients; open right hepatectomy [ORH], 121 patients) were included. Baseline characteristics, including tumor characteristics, perioperative outcomes, and survival outcomes, were compared between the 2 groups. For group comparisons, one-to-one propensity score matching was used to minimize selection biases.

Results

After one-to-one propensity score matching, 25 LRHs were compared to 25 ORHs. Operative time was significantly shorter for the ORH group than for the LRH group (mean, 322.5 versus 379.5 minutes; P = 0.015), whereas the LRH group showed less intraoperative blood loss (P = 0.02) and lower intraoperative transfusion (P = 0.02). Postoperative hospital stays were significantly shorter for the LRH group (mean, 14.5 days versus 20.2 days; P = 0.004). Overall morbidities were significantly lower in the LRH group (1:13, P = 0.00). The cumulative 1-, 3-, and 5-year overall survival rates were 100%, 92.0%, and 92.0%, respectively, for the LRH group, and 84.0%, 80.0%, and 64.0%, respectively, for the ORH group. Furthermore, the cumulative 1-, 3-, and 5-year disease-free survival rates were 96.0%, 80.0%, and 75.3%, respectively, for the LRH group, and 72.0%, 48.0%, and 40.0%, respectively, for the ORH group. The LRH group showed significantly longer disease-free survival (P = 0.009) and overall survival (P = 0.028) than the ORH group.

Conclusion

LRH can be safely performed for hepatocellular carcinoma. LRH was associated with more favorable oncologic outcomes.

Hepatocellular carcinoma (HCC) is the sixth most common malignancy and the fourth leading cause of cancer-related deaths worldwide.1  Most HCCs develop in the background of chronic liver disease, including liver cirrhosis, which makes a surgical approach more demanding. For this reason, resectable cases account for only 25% to 30% of patients.2  Liver transplantation can provide better oncologic outcomes; liver resection, however, is still the treatment of choice because of the donor shortage. Cirrhosis complicates HCC in 80% to 90% of cases worldwide.3,4  Hence, reducing surgical stress while not affecting oncologic outcomes is important in treating HCC. The advantage of laparoscopic liver resection (LLR) is that it is associated with less postoperative pain, early ambulation, early return to oral feeding, and fewer postoperative complications.5  Because of its less invasive nature, LLR can reduce postoperative liver failure and ascites.6 

From 3 consensus meetings,79  minor liver resection has been the standard alternative to open resection. However, major hepatectomy, especially right hepatectomy, for HCC is recommended to be performed in specialized centers. Laparoscopic right hepatectomy (LRH) is technically demanding and has a risk of major vessel injury. Until now, there have been only a few reports on the surgical and oncologic outcomes of major hepatectomy for HCC.1013 

The aim of this study was to evaluate the perioperative and long-term oncologic outcomes of LRH by comparing them with those of open right hepatectomy (ORH) for HCC in well-matched patient groups through a propensity score–matched analysis to minimize selection bias.

After an Institutional Review Board approved the study, the medical records of all patients who underwent right hepatectomy for HCC were retrospectively reviewed. From January 2008 to December 2017, a total of 149 patients underwent right hepatectomy, either through the open or the laparoscopic method. The diagnosis of HCC was entirely based on pathologic examination of resected specimens. Similar inclusion criteria were adopted for both LRH and ORH. Cases with main portal vein invasion and extrahepatic metastasis were excluded from this study. Our institution has a size limitation of 7 cm for LRH.

For LRH, the patient was placed in the reverse Trendelenbeurg position. Five trocars were used (12-mm camera port, two 12-mm working ports, and two 5-mm assistance ports) in all cases. The Glissonian approach was the main method of inflow control. The Cavitron Ultrasonic Surgical Aspirator (Valleylab, Boulder, Colorado) was used in parenchymal dissection. The intermittent Pringle maneuver (15 minutes of clamping and 5 minutes off) was routinely adopted for a clean surgical field. Intra-abdominal pressure was maintained under 12 mmHg and was increased up to 16 mmHg to minimize the blood loss when oozing or minor bleeding was observed. For ORH, an L-shaped incision was used. The Glissonian approach was used for inflow control and the Cavitron Ultrasonic Surgical Aspirator was the main dissection instrument.

After discharge, all patients were followed up according to the Korean HCC guideline.14  Computed tomography (CT) scan was performed every 3 to 4 months during the first 2 years, and every 4 to 6 months thereafter. At each hospital visit, clinical examination, hepatic function tests, and α-fetoprotein level were measured. Recurrence was defined when confirmed on follow-up CT/magnetic resonance imaging.

To minimize the confounding effect, 1:1 propensity score matching (PSM) was performed using a logistic regression model. We matched the following characteristics: age, sex, comorbidity, underlying liver disease, American Society of Anesthesiologists (ASA) grade, blood test, ICGR 15 minutes, α-fetoprotein, previous abdominal operation history, preoperative HCC treatment history, and pathologic findings (tumor size, tumor number). Postoperative morbidity and oncologic outcomes were the primary and secondary end points, respectively. Continuous variables were compared between groups using the Student t-test or Mann-Whitney test, as appropriate. Chi-square test or Fisher exact test was used to compare categoric variables; P < 0.05 was considered statistically significant. The Kaplan-Meier method was used to calculate survival. Survival curves were compared between 2 groups using the log-rank test. All statistical analyses were performed using SPSS version 26.0 (IBM Corp, Armonk, New York).

Clinicopathologic characteristics of the 2 groups before and after PSM are shown in Table 1. Before and after PSM, the ASA score between the 2 groups showed significant difference (P = 0.029 and P = 0.027). The ORH group tended to have larger tumor sizes. After PSM, all of the characteristics except ASA score were comparable.

Operative outcomes are summarized in Table 2. Operative time was significantly shorter for the ORH group than for the LRH group (mean, 322.5 versus 379.5 minutes; P = 0.015), where the LRH group showed less intraoperative blood loss (P = 0.02) and lower rate of intraoperative transfusion (P = 0.02). Postoperative hospital stays were significantly shorter for the LRH group (mean, 14.5 days versus 20.2 days; P = 0.004). Postoperative mortality was not noted in both groups. Overall morbidity rates were significantly lower in the LRH group (1:13, P = 0.00). Grade IIIa complications according to the Clavien-Dindo classification were noted in 1 case in each group.

The median follow-up was 71 months (range, 40–175 months) for the LRH group and 108 months (range, 41–189 months) for the ORH group. Overall survival (OS) and disease-free survival (DFS) curves are presented in Fig. 1. DFS (P = 0.007) was significantly better in the LRH group before matching (Fig. 1A). Both DFS and OS were significantly better in the LRH group after PSM (DFS, P = 0.009; OS, P = 0.028). The cumulative 1-, 3-, and 5-year OS rates were 100%, 92.0%, and 92.0%, respectively, for the LRH group, and 84.0%, 80.0%, and 64.0%, respectively, for the ORH group. Furthermore, the cumulative 1-, 3-, and 5-year DFS rates were 96.0%, 80.0%, and 75.3%, respectively, for the LRH group, and 72.0%, 48.0%, and 40.0%, respectively, for the ORH group (Fig. 1).

Laparoscopic procedures have become an integral part of all surgical fields. LLR also has been rapidly progressing despite its initial slow pace. Most centers have adopted laparoscopic minor hepatectomy for the favorably located malignant lesions.15,16  Major hepatectomy for HCC is gradually being performed, but only by experienced centers because it carries both technical and oncologic concerns. Several centers have reported on the safety and efficacy of LLR and oncologic comparability, mostly for minor LLR. The resection of more than 3 Couinaud segments is considered major hepatectomy for LLR. Only a few centers have published perioperative outcomes and oncologic outcomes with regard to major LLR for the treatment of HCC.12,17,18 

This study demonstrated the feasibility and safety of LRH for HCC in addition to more favorable oncologic outcomes. On PSM results, the LRH group showed less blood loss and shorter hospital stays than the ORH group. Furthermore, overall morbidity rates were significantly lower in the LRH group than in the ORH group. Operative time was longer in the LRH group.

In this study, OS and DFS analysis was performed to confirm whether the perioperative benefits were associated with better survival outcomes. Both before and after PSM, DFS was significantly better in LRH. Although OS before PSM was comparable between LRH and ORH, OS after PSM showed better results in LRH, similarly to DFS. Most reports contain oncologic outcomes of major LLR for HCC, survival was comparable between laparoscopic and open groups, and the trend was favorable to the laparoscopic group without statistical significance.

Our center initiated an LLR program in 2005. The accumulation of experience and the advancement in terms of instruments have elicited a standardization of both major LLR and minor LLR. Left lateral sectionectomy has been performed entirely under laparoscopy since 2013.19  The indication for LLR has been widened and the proportion of LLR has continually increased over time. The indication of the laparoscopic approach for HCC is similar to that of the open approach. With regard to a technical point, the Glissonian approach is adopted as the first considered method for inflow control in most of the cases. The intermittent Pringle maneuver has been routinely used to reduce the blood loss and to maintain a dry surgical field.

Anesthetic management also has been improved. Keeping the central venous pressure as low as possible and peak end-expiratory pressure and the restriction of fluid infusion may help to decrease the intraoperative blood loss.

The present study showed that LRH was associated with less blood loss, shorter hospital stays, and lower complication rates than ORH. The anticipated risk of bleeding under a laparoscopic approach has been one of the major concerns of LLR. Contrary to the initial anticipation, most reports regarding the perioperative outcomes of LLR have demonstrated less blood loss and a low rate of intraoperative transfusion. In addition to the meticulous parenchyma division under the magnified view, maintaining low CVP and the use of the intermittent Pringle maneuver have been the main ways employed to control bleeding in those reports.20,21 

Short-term and long-term oncologic outcomes with regard to LLR were comparable between LMH and OMH groups in most studies.1012,18  Our study, however, demonstrated significantly improved survival benefits in both DFS and OS. The reason for the survival benefit of LRH is assumed to be associated with its low rate of intraoperative transfusion. Several studies on the effects of blood loss and blood transfusion in HCC demonstrated lower survival in the transfusion group,2225  explaining that blood transfusion is related to immunosuppression.2628 

This study has a few limitations despite using PSM to diminish confounding baseline variables between the LRH and ORH groups. It was a retrospective and nonrandomized study in a single center, and the sample size was relatively small to consolidate our findings. A well-designed randomized prospective study involving many centers will be needed to validate the benefits of LRH for HCC.

In conclusion, LRH for HCC showed better oncologic outcomes than ORH. Also, LRH for HCC could be a safe alternative to ORH once it is performed by experienced hepatic surgeons. LRH demonstrated better perioperative outcomes with regard to less blood loss, lower rate of intraoperative blood transfusion, and reduced postoperative morbidity.

We acknowledge the Institutional Review Board at Chonnam National University Hwasun Hospital for approving this study. This study was financially supported by Chonnam National University (grant number 2021-2454).

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Author notes

Rukhsora D. Sultanova and Eun-Kyu Park have contributed equally to this work.