Favorable Long-Term Oncologic Outcomes of Hepatocellular Carcinoma Following Laparoscopic Liver Resection

Abstract

Background:

Reports on the long-term oncologic outcomes of laparoscopic liver resection (LLR) compared to open liver resection (OLR) in patients with hepatocellular carcinoma (HCC) are rare. The aim of this study was to compare the long-term outcomes of LLR and OLR as a treatment for HCC patients.

Patients and Methods:

A total of 125 patients were included in the study (32 patients underwent LLR and 93 underwent OLR). Data were categorized according to operation methods. The primary endpoints were disease-free survival and overall survival. The secondary endpoints were surgical outcomes of LLR for HCC.

Results:

Capsular invasion was more frequent in the LLR group (P = .001). The median follow-up period was 48 months (1–188 month). There were no significant differences between the two groups regarding mortality and morbidity. Hospitalization days were shorter in the LLR group (P = .042). Disease-free 5-year survival of HCC was 40.9% and 47.2% in the LLR and OLR group, respectively (P = .376). Overall 5-year survival for HCC was 96.4% and 96.7% for the LLR and OLR group, respectively (P = .748).

Conclusion:

Our long-term analysis on oncologic aspects confirms the safety of LLR compared to OLR in HCC patients.

Introduction

Despite the rapid increase of laparoscopic operations in abdominal surgery during the last decades, its application in liver surgery is relatively slow.¹ Because most hepatocellular carcinomas (HCCs) develop from chronic liver disease with cirrhosis, it is mandatory to carefully select the optimal candidates for liver resection, even in open surgeries. It is one of the reasons why many surgeons are reluctant to perform laparoscopic liver surgery. Although open liver resection (OLR) is still considered the standard approach for HCC, laparoscopic surgery will prove to be an alternative with cumulating excellent results.

Compared to open procedures, some meta-analyses report that laparoscopic procedures result in more favorable short-term outcomes.^2,3 Although there have been recent reports on the long-term outcome of laparoscopic liver resection (LLR), follow-ups longer than 10 years regarding the surgical results of LLR in HCC patients with cirrhosis are rare.^4–6 Cirrhosis does not only effect short term but also long-term outcomes of hepatic resection in HCC, which leaves laparoscopic approach a field of further study.⁷ Our study analyzed the 13 years experience of LLR for HCC with cirrhosis in a single institute.

To our knowledge, it is not the biggest, but the longest data on LLR for HCC in Korea. The aim of this study was to compare the long-term outcomes of LLR and OLR as a treatment modality for HCC patients in a single institute.

Patients and Methods

This study was approved by the Institutional Review Board at the Yeouido St. Mary's Hospital (IRB number: SC15RIS0100) and was conducted in accordance with the Declaration of Helsinki. A waiver of informed consent was granted for all collected data that preexisted in medical records.

Patient characteristics

Between July 2000 and March 2013, 137 patients with HCC initially underwent hepatic resection as a curative treatment at the Department of Surgery, Yeouido St. Mary's Hospital, The Catholic University of Korea, Seoul. All operations were performed by a single experienced surgeon.

We excluded 12 patients; 3 had extrahepatic metastasis, 3 had adenoma, 2 had combined cholangiocarcinoma-HCC, and 4 had cholangiocarcinoma, all confirmed with permanent pathologic reports. Eventually, 125 patients were included in the study. We divided 125 patients into two groups as follows: 32 patients who underwent LLR and 93 who underwent OLR.

Our selection criteria for liver resection of HCC patients are as follows: compensated chronic liver disease (Child-Pugh class A/B) without signs of severe portal hypertension (esophageal varices less than G2) and with a platelet count of at least 50 × 10⁹/L eligible for liver resection. Resection volume was decided based on the patients' indocyanine green dye retention rate at 15 minutes (ICGR-15) in both the LLR and OLR groups. Patients with ICGR-15 less than 15% were treated with hemihepatectomy or bisegmentectomy, while that of less than 25% were treated with partial resection or monosegmentectomy.

The selection criteria for laparoscopic approach were single tumor in the left lobe without suspicion of middle or left hepatic vein invasion and the peripheral right (segments V, VI) segments with a maximum size of 3 cm.

Complications were graded as severe when patients required reoperation or interventional radiology, or resulted in organ failure or patient death⁸: grades III–V

Surgical procedure

In this study, hepatic resections were described according to the Couinaud classifications.⁹ Bisegmentectomy was defined to resect the section of Brisbane definition¹⁰ or two different segmental resections. One segment resection was defined as dissection of the liver along its theoretical borders, and partial resection was defined as resection of less than one segment of liver. Major resection was defined as more than two Couinaud segment resections.

For laparoscopic surgical resections, patients were approached in the supine position when the tumor was located in left lobe or segment V, while tumor in segment VI was approached in the lateral decubitus position. Pneumoperitoneum was achieved with subumbilical incision and kept below 12 mm Hg. Three or four (from 5 to 12 mm) working ports were generally inserted into the abdomen. We did not perform the Pringle maneuver during laparoscopic resection. During parenchymal transaction in open surgery, intermittent clamping was applied only if needed, with 10 minutes clamping and 5 minutes declamping periods. Intraoperative ultrasonography was applied whenever it was needed to measure the tumor location and resection margin accurately.

As with laparoscopic approaches, parenchyma was dissected with a Harmonic Scalpel (Ethicon Endo-Surgery, United States). Large intraparenchymal structures and portal pedicles were ligated with metal clips. Hepatic artery and portal veins were ligated before parenchymal transection in left hemihepatectomies. At the end of the liver transaction, left hepatic veins were divided with a linear stapler. As for the right side resection, we did not perform any hilar dissections. After transection, fibrin glue was applied to the cut surface. The transected specimen was placed in a plastic bag and extracted through an enlarged port site or a horizontal epigastric incision.

The open hepatectomies were performed using a midline laparotomy or right subcostal incision with extension to the midline; method differed according to tumor locations. Liver mobilization was performed in a routine manner. Parenchymal transection was achieved with Harmonic Scalpel, crushing forceps, or SONOCA (Söring GmbH, Quickborn, Germany). Hepatic parenchymal control of major vessels and bile duct was achieved with clips or suture ligation.

After discharge, all patients were followed up regularly in the outpatient clinic and monitored for recurrence by standard protocols, including monthly checkup of serum alpha-fetoprotein (AFP) level until 6 months postoperation and ultrasound or contrast CT scan every 3–6 months up to 5 years. Chest X-ray was also performed at each visit. Diagnosis of recurrence (intrahepatic or locoregional) was made if there was a radiological evidence of recurrence with or without AFP elevation, supplemented with tissue biopsy if necessary.

Statistical analyses

Disease-free survival was measured from the date of operation to the date of recurrence diagnosis or death without recurrence and was censored for the date of the end of the study period or for the date of the last correspondence (for losses to follow-up). The patient survival rates were compared with Kaplan–Meier plots and log-rank tests. To compare the clinical variables of the two treatment groups, we conducted the χ² test or Fisher's exact test for categorical variables and the student's t-test or Mann–Whitney t-test for continuous variables, after assessing normality. Adjusted P-value of .05 for confounders was considered statistically significant. All statistical analyses were performed with SPSS 18 (SPSS Corp., Chicago, IL).

Results

Operation methods

A total of 32 patients underwent LLR and 24 (75.0%) were confirmed cirrhosis in the final pathology. Among the 93 patients who underwent OLR, 62 patients (66.7%) were confirmed cirrhosis in the final pathology. The operation details of the two groups are summarized in Table 1. Of the 32 laparoscopic procedures, there were 2 hemihepatectomies, 8 bisegmentectomies, 19 monosegmentectomies, and 3 partial resections. In the laparoscopic group, there were five hand-assisted procedures as follows: one left hemihepatectomy, one lateral sectionectomy, and three segmentectomies. There were two conversions from LLR to OLR, and these 2 patients were included in the OLR group. The LLR and OLR did not differ significantly in terms of method of resection (P = .073). Anatomic resection was performed in 23 of 32 patients (71.9%) in the LLR group and in 66 of 93 patients (71.0%) in the OLR group (P = .901).

Table 1.

Operation Methods of LLR and OLR

	LLR (n = 32), %	OLR (n = 93), %	P
Hemihepatectomy	2 (6.3)	14 (15.1)	.073
Bisegmentectomy	8 (25.0)	24 (25.8)
Monosegmentectomy	19 (59.2)	34 (36.6)
Partial resection	3 (9.4)	21 (22.6)
Anatomic resection	21 (65.6)	66 (70.9)	.901

LLR, laparoscopic liver resection; OLR, open liver resection.

Perioperative clinical data

Perioperative clinical data are described in Table 2. Comparing the LLR and OLR group, there were no significant differences in age, gender, hepatitis B infection, tumor marker, and the number of transcatheter arterial chemoembolization (TACE) before resection. The two groups of patients had similar liver function in terms of serum total bilirubin levels and Child-Pugh classification. Indocyanine green retention rate at 15 minutes was higher in the LLR group (P = .036).

Table 2.

Perioperative Clinical Data of LLR and OLR

	LLR (n = 32)	OLR (n = 93)	P
Age^a (years)	55.6 ± 11.5	56.9 ± 9.6	.596
Gender (man/woman)	26/6	80/13	.517
BMI (Kg/m²)	25.2 ± 4.4	24.8 ± 8.6	.662
HBs Ag (±)	17/15	61/32	.29
Total bilirubin^a (mg/dL)	0.8 ± 0.6	1.0 ± 0.7	.265
CTP classification (A/B)	28/2	83/9	.605
ICG R-15 (%)	10.6 ± 11.8	8.2 ± 5.8	.036
Preoperative TACE (none/single/multiple)	0/26/5	5/68/20	.308
AFP^a (ng/mL)	71.04 ± 132.9	89.9 ± 173.3	.188
AFP (≥100 ng/mL/<100 ng/mL)	8/23	21/69	.781
Follow-up (month, median)	64.0 ± 48.0	54.6 ± 37.0	.266

mean ± SD.

AFP, serum alpha-fetoprotein; BMI, body mass index; CTP, child-Pugh class; HBs Ag, hepatitis B virus surface antigen; ICG R-15, indocyanine green dye retention rate at 15 minutes; LLR, laparoscopic liver resection; OLR, open liver resection; TACE, transcatheter arterial chemoembolization.

Pathologic factors

Pathologic factors are summarized in Table 3. There were no significant differences in tumor-related factors between the two groups: maximum tumor diameter (3.1 ± 1.9 versus 3.0 ± 2.3 cm, P = .863), tumor numbers, pathologic cirrhosis, microvascular invasion, and satellite nodules. There were also no significant differences between the two groups regarding resection margin status, which was negative in all 125 patients. Capsular invasion was more frequent in the LLR group (87.5% versus 50.6%, P = .001).

Table 3.

Tumor Characteristics of the LLR Group and OLR Group

	LLR (n = 32)	OLR (n = 93)	P
Tumor number (single/multiple)	31/1	85/8	.301
Cirrhosis (±)	24/8	62/28	.515
Microvascular invasion (±)	0/27	5/83	.205
Capsular invasion (±)	21/3	44/43	.001
Complete tumor necrosis (±)	4/22	10/74	.737
Satellite nodule (±)	3/22	2/79	.084
Resection margin (≥1 cm/<1 cm)	12/13	32/50	.425
Largest tumor size^a (median, cm)	3.1 ± 1.9 (3.0)	3.02 ± 2.3 (2.5)	.863

mean ± SD (median).

LLR, laparoscopic liver resection; OLR, open liver resection.

Short-term surgical outcome

Short-term surgical outcomes are summarized in Table 4. The mean operating time was not significantly different between the two groups. More transfusions were required in the OLR group, but did not show significant difference. Length of hospital stay was longer in the OLR group (P = .043). There was no hospital mortality in both groups. The overall morbidity rate was 18.8% in the LLR group and 25.8% in the OLR group (P = .421). The occurrence of severe complication was higher in the OLR group, but did not show significant difference (6.3% versus 20.4%, P = .208).

Table 4.

Postoperative Courses of LLR and OLR

	LLR (n = 32)	OLR (n = 93)	P
Hospital mortality	0	0	−
Overall morbidity	6 (18.8%)	24 (25.8%)	.421
Severe complication	3 (6.3%)	19 (20.4%)	.208
Bile leakage	0	2
Bleeding	1	4
Pleural effusion	1	8
SSI	0	1
Cardiopulmonary	1	3
PHLF	0	1
Operative time^a (min)	321.2 ± 87.9	348.4 ± 72.6	0.456
Transfusion (±)	2/30	18/75	0.068
Hospital day^a	7.2 ± 3.5	12.2 ± 6.6	0.045

Severe complication: Dindo classification III-V (6).

mean ± SD.

LLR, laparoscopic liver resection; OLR, open liver resection; PHLF, post hepatectomy liver failure; SSI, surgical site infection.

Recurrence

Median follow-up time to recurrence was 41.0 ± 4.7 months (range 2–168) in 13 patients (40.6%) who underwent LLR. Among the 93 patients who underwent OLR, 47 patients (50.5%) had a recurrence in 24.0 ± 3.1 months (range 1–137).

Recurrence within 1 year after operation occurred in 3 (9.3%) patients of the LLR group and 19 (20.4%) patients of the OLR group, respectively (P = .218). There were no significant differences between the two groups in recurrence pattern and the number of metastatic tumors in the liver (Table 5).

Table 5.

Recurrence Characteristics

	LLR (n = 32)	OLR (n = 93)	P
Recurrence	13 (40.6%)	47 (50.5%)	0.825
Within 1 year recurrence	3 (9.4%)	19 (20.4%)	0.218
Hepatic recurrence	12 (37.5%)	39 (41.9%)	0.668
Locoregional recurrence	1 (3.1%)	8 (8.6%)	0.08
Number of liver recurrences (single/multiple)	9/2	26/13	0.468

LLR, laparoscopic liver resection; OLR, open liver resection.

Survival after liver resection

Disease-free survival rates in the LLR group were as follows: 1-year disease-free survival 83.3%, 3-year disease-free survival 49.1%, and 5-year disease-free survival 40.9%. Corresponding rates in the OLR group were 76.2%, 56.5%, and 47.2%, respectively (P = .376; Fig. 1). As for overall survival rates, 1-year survival was 96.4%, 3-year survival 95.6%, and 5-year survival 91.8% in the LLR group. The 1-, 3-, and 5-year survival rates in the OLR group were 96.7%, 95.6%, and 90.3%, respectively (P = .748; Fig. 2).

FIG. 1.

Overall disease-free survival after LLR and OLR for HCC (P = .376). HCC, hepatocellular carcinoma; LLR, laparoscopic liver resection; OLR, open liver resection.

FIG. 2.

Overall survival after LLR and OLR for HCC (P = .748). HCC, hepatocellular carcinoma; LLR, laparoscopic liver resection; OLR, open liver resection.

Ten-year disease-free survival rate in the LLR group was 40.9%, while that of OLR was 28.9%. Overall survival rate at the 10th year since operation was 91.8% in the LLR group and 86.4% in the OLR group.

Discussion

This series of 32 LLRs in selected patients with HCC revealed favorable long-term oncologic outcomes compared to open surgery. In addition, this study showed the relative safety of LLR, with zero mortality and comparable operative morbidity (18.8%) in comparison with open surgery (25.8%).

Recently, two meta-analyses reported affirmative results of laparoscopic resection of HCC compared to open surgery regarding short-term surgical outcomes. This meta-analysis of 213 patients showed that LLR for HCC is superior to OLR in terms of perioperative results and does not compromise oncologic outcomes.¹¹ Twaij et al.² suggested that a laparoscopic approach, compared to open surgery, may result in improved short-term outcomes in the form of wider resection margins, reduced intraoperative blood loss, and need for transfusions, as well as reduced morbidity rates and shorter lengths of stay. High intraperitoneal pressure caused by CO2 pneumoperitoneum was considered to be one of the major reasons for reduced blood loss in LLR for HCC.⁶ Concurrent with the reports, our study also showed that more transfusions were required in the OLR group, although it was not significantly different (6.3% versus 19.3% P = .06).

Our study showed favorable oncologic outcome during the 13-year follow-up period. There were no differences in overall survival and disease-free survival between the two groups. Although there were no statistically significant differences regarding 10-year disease-free survival and overall survival, the LLR group tended to show better results. These are not only concurrent with the previous studies but also results with the longest follow-up period of HCC with liver cirrhosis.^6,12–14 Our higher overall survival is likely to be due to our aggressive multimodal treatment, such as TACE and radiofrequency ablation (RFA), on recurred HCC.

The main concern about the use of laparoscopic procedure for malignancies is the risk of inadequate tumor resection.¹⁵ No positive resection margins were to be seen in our consecutive 32 laparoscopic resections for HCC. These are excellent results compared to other previous reports regarding resective margin. It can be partly explained by the routine use of intraoperative laparoscopic ultrasonography to locate the tumor, which made it possible to trace the intended margin.¹⁶

It is true that LLR for HCC is not accepted as a worldwide routine procedure, but for lateral lesions, the potential for LLR to become a treatment of choice for surgeons is promising.¹⁷ It is also encouraging that our results were relatively favorable despite, including restrictive conditions such as cirrhosis.

Favorable postoperative morbidities of LLR were explained by the minimization of damage to the abdominal wall, which allows avoiding of large collateral vein interruptions and exposure of the abdominal viscera; hence, with the dual benefit of less need for fluid infusion and improved reabsorption of ascites, the small incision limits the drainage of ascites through the wall and, thereby, lowers the risk of infection.¹⁸ It is also known that CO2 pneumoperitoneum lowers local immune reactions carried out by tumor necrosis factor-α or nuclear factor kappa-light-chain-enhancer of activated B cells.¹⁹ Our series did not show LLR's statistical superiority over OLR with regard to surgical complications, but the overall morbidity and severe complication rates were better in the LLR group. It is expected that improvement in instruments and technology will lead to even better outcomes. LLR will extend the surgical limitations conferred by tumor size, hepatic reserve function, and tumor locations.

Many reports, including our study, have the limitation of small study groups and selection bias, rendering it difficult to drive robust conclusions. In the previous mentioned meta-analysis studies,^2,11 the authors pointed out that all studies concerning LLR of HCC were nonrandomized cohorts of single centers. They mention that the proficiency of surgeons and selection bias could weaken the potential generalizability of the results. Although our study did not show significant differences between the OLR group and the LLR group regarding operative methods, demographics, clinical data, and tumor characteristics, it still was conducted with nonrandomized matching, leaving space for the possibility of selection bias in the LLR group.

Although our study included highly selective patients with HCC, these results are sufficient to prove the safety and effectiveness of laparoscopic liver surgery for HCC. In the future, LLR for HCC in selected patients will become a routine procedure for liver surgeries.

In conclusion, the long-term analysis on oncologic aspects of our study confirmed the safety of LLR compared to OLR in HCC patients.

Footnotes

Disclosure Statement

No competing financial interests exist.

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