Surg Endosc DOI 10.1007/s00464-014-3980-1
and Other Interventional Techniques
Oncological and surgical results of laparoscopic versus open liver resection for HCC less than 5 cm: case-matched analysis Sam-Youl Yoon • Ki-Hun Kim • Dong-Hwan Jung Ami Yu • Sung-Gyu Lee
•
Received: 4 July 2014 / Accepted: 25 October 2014 Ó Springer Science+Business Media New York 2014
Abstract Background The purpose of this study is the evaluation of the surgical and oncological results of laparoscopic liver resection (LLR) for hepatocellular carcinoma (HCC) by comparing laparoscopic and open liver resection (OLR) in the treatment of this disease. Retrospective analysis of laparoscopic and OLR for HCC (\5 cm) performed over a 4-year period was conducted. The LLR was done by a single surgeon. Methods The study was performed on patients who received liver resection for HCC between July 2007 and August 2011 in our institution. Propensity-based matched analyses were used to account for operative method selection biases. During the 4 years, 1,050 patients with HCC received an operation. Among them patients who never received TACE or RFA before surgery and had HCC (\5 cm) were selected for this study. Results 174 patients had OLR, and 58 patients underwent LLR. Patients who received LLR had lower operative time, transfusion rate, complication rate, and shorter hospital days. There were significant differences in hospital
S.-Y. Yoon Department of Surgery, Korea University Ansan Medical Center, Korea University College of Medicine, Gyeonggi-do, Korea e-mail: [email protected] K.-H. Kim (&) D.-H. Jung S.-G. Lee Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, 388-1 Pungnap-dong, Songpa-gu, Seoul 138-736, Korea e-mail: [email protected] A. Yu Biostatistical Consulting Lab, Korea University Ansan Hospital Medical Science Research Center, Gyeonggi-do, Korea
mortality and morbidity between the two groups. Dietary recovery was relatively fast in the group of LLR. Overall and disease-free survival rates during the 4 years were also not significantly different between the two groups. Conclusions LLR is a developing and safe technique in a select group of patients including those with malignancies, and use of this procedure is associated with short hospital stays, a rapid return to a normal diet, full mobility, and minimal morbidity, with acceptable oncological parameters. It may be an optimal method of hepatectomy in HCC (\5 cm). Further, long-term follow-up should be acquired for adequate evaluation for survival. Keywords carcinoma
Laparoscopic hepatectomy Hepatocellular
Potentially curative therapy for hepatocellular carcinoma (HCC) includes liver resection, local ablation, and liver transplantation [1]. The possibility of repeated surgery for cancer recurrence or liver transplantation is usually high in patients with HCC. The laparoscopic approach results in less postoperative adhesion than open abdominal surgery, decreasing the difficulty of dissection in future operations [2]. The reasons for this are presumed technical difficulty related to liver mobilization, controlling hemorrhage, vascular control, inability to perform manual palpation, working with the deeper regions of the liver, and intraoperative hazards such as gas embolism, massive bleeding, and bile duct injury [3, 4]. For these reasons, LLR has only been indicated for small (\5 cm) and easily accessible lesions (segments II, III, V, VI, and the inferior part of IV) [5, 6]. But, in our institute, with the refinements in laparoscopic instruments and advances in surgical experience, LLR has become a common method of treatment for HCC.
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The authors reviewed our 4-year results of laparoscopic liver resection (LLR) for HCC and compared them with open liver resection (OLR). The authors limited our study to HCC because it constitutes our major portion of liver resection cases and the inclusion of other malignant tumors would make assessment of recurrence and survival difficult. A 3–1 propensity score-matched analysis was done to investigate the surgical and oncologic outcomes of patients with HCC during the same period. We believe that this large volume retrospective study gives us the best evidence for using the laparoscopic approach for HCC with regard to the oncologic aspect.
Materials and methods Patient selection Between July 2007 and August 2011, 1,050 patients received liver resection at Asan Medical Centre for HCC. Among them, patients with single-lesion HCC (\5 cm) who never received liver resection, trans-arterial chemoembolization (TACE) and radiofrequency ablation (RFA) before surgery were selected for this study to exclude the influence of TACE and RFA. There were 318 cases of OLR and 74 cases of LLR. After performing a 3–1 propensity score-matched analysis, there were 174 cases of OLR and 58 cases of LLR. LLR has been carried out since July 2007 by a single experienced surgeon responsible for liver donor hepatectomy and hepato-biliary surgery over 10 years. OLRs were performed by a hepato-biliary team of extensive experienced surgeons with a standardized protocol. The indications for LLR were similar to indications for OLR. The main concerns of surgical indication were preoperative liver function and type of liver resection. Location of the tumor in a peripheral site or not was not a significant consideration. Whether LLR or not was dependent on the surgeon’s preference. Anatomical liver resection and functioning of the remnant liver were preferentially considered in both LLR and OLR. The localization of HCC was done by Couinaud’s classification. The patients undergoing LLR were compared to patients who underwent OLR with respect to preoperative, intraoperative, postoperative, and oncologic aspects. Surgical procedure Laparoscopic liver resection Laparoscopy was then performed under CO2 pneumoperitoneum. The patient was placed supine in the 30°D reversed Trendelenburg position, with the surgeon standing between the patient’s legs. Five trocars were usually
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inserted, with the middle trocar used for the main working device. Exploration of the extent of the tumor and determination of its relationship with the vascular anatomy and other tumors in the liver were performed using intraoperative ultrasonography. Liver traction was done by atraumatic graspers (Direct Drive laparoscopic grasper; Applied Medical Resources, Rancho Santa Margarita, California, USA). These instruments can help pull the liver atraumatically during division of the hepatic parenchyma. Transection of liver parenchyma was performed using Harmonic ScalpelTM (Ethicon Endosurgery, Cincinnati, Ohio, USA). The deep hepatic parenchyma was divided using a laparoscopic CUSA. During LLR, en masse or blind stapling of the hepatic parenchyma cannot be performed to achieve meticulous haemostasis and biliostasis. In 4 cases of right hepatectomy (RH) and 5 cases of right posterior segmentectomy (RPS), a ‘hanging-over’ maneuver was used, which results in easier, more accurate hepatectomy, and provides a better view of the hepatic veins and Glisson’s pedicles. The benefit of ‘hanging-over’ maneuver was better exposure and hemostasis of the deeper plane of parenchyma (Fig. 1A). Small branches of Glisson’s pedicles were clipped by metal clip, and large Glisson’s pedicles were ligated using a knot pusher (5 mm knot guide; MGB Endoscopy Corporation, Seoul, Korea) or endoscopic linear stapler (Echelon FlexTM; Ethicon Endosurgery, Cincinnati, USA) with 45 mm gold cartridge (Fig. 1B). After parenchymal dissection, endoscopic linear stapler (Echelon FlexTM; Ethicon Endosurgery, Cincinnati, USA) with 45 mm white cartridge was used to ligate the main hepatic veins (Fig. 1C). Once free, the specimen was placed in an endobag by insertion through a 12-mm trocar and retrieved through a 10-cm Pfannenstiel incision.
Statistical analysis We performed a 3–1 propensity score-matched analysis. Propensity scores were computed by modeling a logistic regression with the dependent variable as the odds of undergoing LLR, and the independent variables as age, sex, underlying liver disease, ICG, PT, and pathology. For statistical analysis, Two-way ANOVA test, Friedman test, Cochran-Mantel-Haenzel test, and Stratified log-rank test (for survival rates) were used. Data were summarized as frequencies and proportions, and differences between groups were evaluated by the Cochran-Mantel-Haenzel test for categorical variables or Two-way ANOVA and Friedman test for continuous variables. Statistical significance was set at P \ 0.05. SPSS version 20 (SPSS, Chicago, Illinois, USA) and SAS V9.3 were used for all statistical analyses.
Surg Endosc Table 1 Preoperative patient characteristic and laboratory findings OLR (n = 174)
LLR (n = 58)
55.0 (49–61)
54.3 (49–63)
Age Female/Male (Ratio)
44/130 (0.34)
Pa 0.64b 0.23c
13/45 (0.28)
0.71c
Liver disease HBV
165 (94.8 %)
HCV
6 (3.5 %)
54 (93.1 %) 3 (5.2 %)
Alcoholic hepatitis
3 (1.7 %)
1 (1.7 %)
ICG 15 (%) AFP level (ng/mL)
12.4 (8.9–15.2) 469 (3.2–200)
12.14 (8.6–14) 2553 (3.1–132)
Platelets 9 103/ mm3
153 (121–192)
152 (117–187)
0.68b 1.00 1.00
INR
1.05 (0.88–1.39)
1.07 (0.95–1.90)
0.50
Total Bilirubin (mg/dl)
1.02 (0.8–1.2)
1.06 (1.01–1.1)
0.06
Albumin (g/dL)
3.89 (3.7–4.2)
3.84 (3.6–4.1)
CTP score A B
0.13 0.72
158 (90.8 %) 16 (9.2 %)
53 (91.4 %) 5 (8.6 %)
Values are median (interquartile range) except gender ratio and liver disease OLR open liver resection, LLR laparoscopic liver resection, AST aspartate aminotransferase, ALT alanine aminotransferase, ICG 15 indocyanine green retention rate at 15 min a
Friedman test, except
b
Two-way ANOVA
c
Cochran-Mantel-Haenzel test
Comparison of the surgical parameters relating to the operation
Fig. 1 Procedures of laparoscopic liver resection. A ‘Hanging over’ maneuver, B Ligation of Glisson’s pedicles by Hem-o-lok and endoscopic linear stapler with 45 mm gold cartridge, C Hepatic vein cutting by endoscopic linear stapler with 45 mm white cartridge
Results Preoperative characteristics comparison of between OLR and LLR group Demographic data of the clinicopathological features in the OLR and LLR groups are shown in Table 1. There were no significant differences between the two groups in age, underlying disease, ICG, AFP, platelets, INR, bilirubin, and albumin. 158 patients of OLR and 53 patients of LLR were CTP grade A.
In the OLR group, 115 (66.1 %) were anatomical hepatectomy (more than 2 segments). These include 20 RH, 24 right anterior segmentectomy (RAS), 38 RPS, 13 left hepatectomy (LH), 6 central bisegmentectomy (CBS), and 8 left lateral segmentectomy (LLS). 43 (74.1 %) were anatomical hepatectomy (more than 2 segments) in the LLR group. These included 4 right hepatectomy (LRH), 5 right posterior segmentectomy (LRPS), 6 left hepatectomy (LLH), and 28 left lateral segmentectomy (LLLS). The mean duration of operation was 255 (200–300) mins in the OLR group and 207 (146–251) mins in the LLR group (P = 0.00). The transfusion rate was 13 (7.5 %) and 2 (3.4 %), respectively, and significantly high in OLR (P = 0.04). All LLRs were successful. There were no notable differences in operative times between the two groups, and there was no case of conversion to open surgery (Table 2, 3). Postoperatively, the patients started diet significantly earlier in the LLR group: 2.4 (1–4) days of postoperative fasting in the OLR group and 2.8 (1–5) days of
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Surg Endosc Table 2 Type of liver resection Type of liver resection
OLR (n = 174)
LLR (n = 58)
RH
20
RH
RAS
24
RPS
38
RPS
LH
13
LH
Table 3 Surgical outcomes of and oncologic finding by operative type LLR (n = 58)
Operation time (mins)a
255 (200–300)
207 (146–251)
0.00
5
Transfusion
13 (7.5 %)
2 (3.4 %)
0.04d
6
2.8 (1–5) 15 (8–22)
2.4 (1–4) 9.2 (6–14)
0.01 0.00
4
LLS
8
LLS
28
Recovery to diet (days) Hospital day (days)
Partial hepatectomy
59
Partial hepactectomy
15
Complicationb
Central Bisegmentectomy
6
Open conversion
0
RH right hepatectomy, RAS right anterior segmentectomy, RPS right posterior segmentectomy, LH left hepatectomy, LLS left lateral segmentectomy
postoperative fasting in the LLR group (P = 0.01), and the patients of LLR recovered more rapidly, which consequently resulted in shorter hospitalization: 15 (8–22) days in the OLR group and 9.2 (6–14) days in the LLR group (P = 0.00). The resumption of diet was determined by recovery of bowel sound and normalization of bowel gas distribution on simple abdominal X-ray. The criteria of discharge were composed of dietary recovery, normalization of laboratory findings, and no surgical complication. The LLR group had a 6.9 % complication rate, and the OLR group had a complication rate of 22.4 % (P = 0.02). Grade I and II complication (Clivein–Dindo) was 32 and 3 in the OLR group and 3 and 1 in the LLR group, respectively (P = 0.02). Significant postoperative complications (IIIa) occurred in 3 cases of OLR and 1 case of LLR. A bile leak requiring interventional drainage or stent placement was the most common complication (n = 4; OLR, n = 1; LLR). Bleeding requiring interventional embolization was one case in OLR. Severe postoperative complication requiring operation (IIIb) occurred in 1 case of OLR. (Table 3). Comparison of the treatment outcomes in oncologic aspect between LLR and OLR group Recurrences related to laparoscopy, such as peritoneal dissemination and port-site recurrences, were not observed in the LLR group. To investigate the oncologic outcomes between the laparoscopic and open group, the authors compared data on surgical margin, margin-positive rate, and tumor recurrence. On the pathologic aspect, there were significant differences in the safety resection margin between the two groups: 1.12 (0.3–2.0) cm in the OLR
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Pc
OLR (n = 174)
0.02d
I
32
3
II
3
1
IIIa
3
1
IIIb
2
None
Descriptions of complication I
Wound infection (32)
Wound infection (3)
II
Intra-abdominal fluid collection (1) Bile leakage (2)
Bile leakage (1)
IIIa
Bile leakage (2) Bleeding (1) Bleeding (2)
Bile leakage (1) None
3 (1.7 %)
0 (0.0 %)
1.12 (0.3–2.0)
2.03 (0.8–3.0)
0.01
3.04 (0.20–4.9)
2.87 (0.70–4.9)
0.23
IIIb Resection margin (?) Resection margin (cm)
a
Tumor size (cm)
0.03d
Recurrence (%)
31 (17.8 %)
16 (27.6 %)
0.10
Edmonson–Steiner grade
OLR (n = 174)
LLR (n = 58)
0.25
I II
6 (3.4 %) 40 (23.0 %)
3 (5.2 %) 19 (32.8 %)
III
79 (45.4 %)
29 (50.0 %)
IV
33 (19.0 %)
3 (5.2 %)
16 (9.2 %)
4 (6.8 %)
Lymphovascular invasion
4 (2.3 %)
4 (6.9 %)
0.62
Capsular invasion
11 (6.3 %)
5 (8.6 %)
0.41
Necrotic nodule Microinvasion
Values are median (range), except operation time and resection margin (cm) a
Values are median (interquartile range)
b
Complication was categorized by Clavien–Dindo classification
c
Friedman test, except
d
Cochran-Mantel-Haenzel test
group and 2.03 (0.8–3.0) cm in the LLR group (P = 0.01). There were 3 cases (1.7 %) of resection margin involvement in the OLR group in contrast to no cases in the LLR group (P = 0.03). There was also no significant difference
Surg Endosc
in recurrence of HCC between the two groups: 31 cases (17.8 %) in the OLR group and 16 cases (27.6 %) in the LLR group (P = 0.10). With regard to the pathologic aspect, the most common Edmonson-Steiner grade was III in both groups. Grade II and III were 40 (23.0 %) and 79 (45.4 %) in the OLR group and 19 (32.8 %) and 29 (50.0 %) in the LLR group, respectively (P = 0.25). The 1-, 2-, 3-, and 4-year overall survival rates for the ORL and LLR groups were 98.0, 93.0, 84.0, and 68 % and 95.0, 92.0, 86.0, and 86.0 %, respectively (Fig. 2, P = 0.48). The 1-, 2-, 3- and 4-year disease-free survival rates for the ORL and LLR groups were 88.0, 79.0, 62.0, and 62.0 % and 82.0, 63.0, 56.0, and 56.0 %, respectively (Fig. 3, P = 0.31). Thus, there was no significant difference between the two groups in overall and disease-free survival at 1-, 2-, 3-, and 4-years, respectively.
Discussion On this study, more objective and adequate comparative analysis with the two groups (LLR and OLR) could be deduced. This is probably because the OLR could only be carried out by surgical teams with expertise in liver surgery and liver transplantation under the standardized protocol and with standardized methods [7]. In the authors’
Fig. 2 4-year overall survival for the two groups The 4-year overall survival rates for ORL and LLR groups were 68.0 and 86.0 %, respectively (P = 0.48). There were no statistically significant differences between LLR and OLR in the overall survival during 4 years
Fig. 3 4-year disease-free survival for the two groups The 4-year disease-free survival rates for ORL and LLR groups were 62.0 and 56.0 %, respectively (P = 0.31). There were no statistically significant differences between LLR and OLR in the disease-free survival during 4 years
institution, more than 700 OLR, 300 living donor liver transplantations (LDLT), and 35 LLR are done annually. This study shows conclusively that LLR appears to be comparable or superior to OLR regardless of the location of the tumor. The LLR group had not only a better cosmetic effect, but also had a comparable result on oncologic aspect. With regard to anatomical hepatectomy, anatomical hepatectomy of more than 2 segments was 115 (66.1 %) in the OLR group and 43 (74.1 %) in the LLR group. In other studies, most cases in the laparoscopic group were segmentectomies or subsegmentectomies located in segments II, III, IV, VI, or VI. Also, tumor size, type, and location are important in determining indications for LLR for HCC [8–11]. It has been reported that HCC with small size (5 \ cm) located in superficial and peripheral sites could be an indication for LLR. But, several retrospective studies have shown that the survival rate of patients operated on by anatomical resection was superior to that of patients operated on by non-anatomical resection, according to remnant function [12, 13]. In our institute, anatomical liver resection is preferred by the surgical team if the remnant liver function is tolerable. The laparoscopic surgeon also considers anatomical liver resection to be important in LLR. Intraoperative ultrasonography can help with the demarcation of segments and the identification of the tumor.
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As with many institutions, the conversion rate to open hepatectomy in our study was zero in LLR; in the literature, general conversion rates ranged between 0 and 20 % [14, 15]. Once the LLR plan for a patient was determined, operative decision making started with high-quality crosssectional 3D CT imaging according to the liver surgeon’s needs. In the case of LH or poor demarcation of the main mass, magnetic resonance imaging can help the surgeon understand the biliary anatomy and boundaries of the main mass. Therefore, good planning before an LLR operation can prevent conversion to open hepatectomy. Consistent with previous studies, the authors have seen less transfusion rate, shorter hospital stays, and fewer complications during the postoperative course with the laparoscopic approach, but controversial results in operation time [3, 16–19]. Advantages of LLR include decreased blood loss and transfusion rate. Intraoperative pneumoperitoneum and image magnification may help reduce blood loss and provide easier access to the hepatic vein and Glisson’s pedicles [20]. Blood loss has been showed to have a prejudicial impact on both short- and long-term outcomes. It has also been reported that perioperative transfusion is associated with poor prognosis [21–23]. Better integrity of the abdominal wall may be attributable to early discharge from hospital and to reduction of pain at the surgical site. Rapid recovery from surgery and an earlier discharge from the hospital provide further evidence for the safety and feasibility of LLR. Actually, some institutes including our institute have even performed LLR on liver graft retrieval for LDLT, the performance of which predicts the potentially enormous value of LLR in liver surgery [1, 24]. With the oncologic aspect, there were also no significant differences in tumor size, tumor pathologic grade, pathologic invasiveness, recurrence, 4-year survival, and eventual 4-year disease-free survival rate. Most series in the literature revealed no difference in resection margin involvement rate and distance from resection margin between LLR and OLR, but our study revealed a significant higher margin involvement and shorter distance from resection margin in the ORL group [25, 26]. This may be due to a patient selection bias because of choosing to perform OLR for tumors located close to hilum, inferior vena cava, or major hepatic veins. Although the lack of palpation in LLR may decrease the surgery margin, when an anatomic resection is planned and intraoperative ultrasound is used to locate the purposed margin and the tumor could also be achieved laparoscopically. Several studies in the literature reported the long-term result of laparoscopic hepatectomy for HCC. The reported 5-year overall survival of laparoscopic hepatectomy for HCC ranged from 50 to 75 %, and the 5-year disease-free survival ranged from 24 to 45.6 % [6, 14]. The 4-year
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overall and disease-free survival in the laparoscopic hepatectomy for HCC (\5 cm) in this study were 86.0 and 56.0 %, respectively. It is explained by restricted indication as HCC (\5 cm) without treatment history of TACE, RFA, or surgery. So, it must be noticed that the results were based on the selected patients of relative early stage of tumor in our study. The conclusions of this retrospective analysis are limited by several factors. More detailed longterm studies especially in the form of RCTs will be needed to confirm our conclusion. Despite improvement in surgical methods and medications to treat HCC over the past few decades, recurrence and metastasis are still frequently seen, and the 5-year survival rate of patients with HCC is still quite low [27, 28]. Resection is safer and superior to in loco-regional treatment. Especially, LLR can result in a smaller scar and reduced intraperitoneal adhesions. Therefore, LLR can facilitate reoperation for recurrent HCC and can be a life-prolonging bridge operation before transplantation [29]. But, laparoscopic major hepatectomy still remains a technically demanding procedure and should only be performed by experienced hepato-biliary surgeons with expertise in open liver section and laparoscopic surgery after adequate training [30]. Conclusively, LLR is a safe and feasible alternative for selected patients with HCC (\5 cm) and was shown not to increase the tumor recurrence risk or adversely affect oncologic outcomes. LLR is a safe and developing technique in a select group of patients with HCC. LLR has the advantages of rapid recovery and low morbidity with acceptable oncological and pathological parameters. It may be an optimal and promising method of hepatectomy in HCC (\5 cm). Longer follow-up periods are needed to make more definite conclusions about the comparative survival probability of the two groups (LLR and OLR).
Conflict of interest
The authors have no conflicts of interest.
Disclosures Sam-Youl Yoon, Ki-Hun Kim, Dong-Hwan Jung, Sung-Gyu Lee, and Ami Yu has no conflicts of interest or financial ties to disclose.
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and Other Interventional Techniques
Oncological and surgical results of laparoscopic versus open liver resection for HCC less than 5 cm: case-matched analysis Sam-Youl Yoon • Ki-Hun Kim • Dong-Hwan Jung Ami Yu • Sung-Gyu Lee
•
Received: 4 July 2014 / Accepted: 25 October 2014 Ó Springer Science+Business Media New York 2014
Abstract Background The purpose of this study is the evaluation of the surgical and oncological results of laparoscopic liver resection (LLR) for hepatocellular carcinoma (HCC) by comparing laparoscopic and open liver resection (OLR) in the treatment of this disease. Retrospective analysis of laparoscopic and OLR for HCC (\5 cm) performed over a 4-year period was conducted. The LLR was done by a single surgeon. Methods The study was performed on patients who received liver resection for HCC between July 2007 and August 2011 in our institution. Propensity-based matched analyses were used to account for operative method selection biases. During the 4 years, 1,050 patients with HCC received an operation. Among them patients who never received TACE or RFA before surgery and had HCC (\5 cm) were selected for this study. Results 174 patients had OLR, and 58 patients underwent LLR. Patients who received LLR had lower operative time, transfusion rate, complication rate, and shorter hospital days. There were significant differences in hospital
S.-Y. Yoon Department of Surgery, Korea University Ansan Medical Center, Korea University College of Medicine, Gyeonggi-do, Korea e-mail: [email protected] K.-H. Kim (&) D.-H. Jung S.-G. Lee Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, 388-1 Pungnap-dong, Songpa-gu, Seoul 138-736, Korea e-mail: [email protected] A. Yu Biostatistical Consulting Lab, Korea University Ansan Hospital Medical Science Research Center, Gyeonggi-do, Korea
mortality and morbidity between the two groups. Dietary recovery was relatively fast in the group of LLR. Overall and disease-free survival rates during the 4 years were also not significantly different between the two groups. Conclusions LLR is a developing and safe technique in a select group of patients including those with malignancies, and use of this procedure is associated with short hospital stays, a rapid return to a normal diet, full mobility, and minimal morbidity, with acceptable oncological parameters. It may be an optimal method of hepatectomy in HCC (\5 cm). Further, long-term follow-up should be acquired for adequate evaluation for survival. Keywords carcinoma
Laparoscopic hepatectomy Hepatocellular
Potentially curative therapy for hepatocellular carcinoma (HCC) includes liver resection, local ablation, and liver transplantation [1]. The possibility of repeated surgery for cancer recurrence or liver transplantation is usually high in patients with HCC. The laparoscopic approach results in less postoperative adhesion than open abdominal surgery, decreasing the difficulty of dissection in future operations [2]. The reasons for this are presumed technical difficulty related to liver mobilization, controlling hemorrhage, vascular control, inability to perform manual palpation, working with the deeper regions of the liver, and intraoperative hazards such as gas embolism, massive bleeding, and bile duct injury [3, 4]. For these reasons, LLR has only been indicated for small (\5 cm) and easily accessible lesions (segments II, III, V, VI, and the inferior part of IV) [5, 6]. But, in our institute, with the refinements in laparoscopic instruments and advances in surgical experience, LLR has become a common method of treatment for HCC.
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The authors reviewed our 4-year results of laparoscopic liver resection (LLR) for HCC and compared them with open liver resection (OLR). The authors limited our study to HCC because it constitutes our major portion of liver resection cases and the inclusion of other malignant tumors would make assessment of recurrence and survival difficult. A 3–1 propensity score-matched analysis was done to investigate the surgical and oncologic outcomes of patients with HCC during the same period. We believe that this large volume retrospective study gives us the best evidence for using the laparoscopic approach for HCC with regard to the oncologic aspect.
Materials and methods Patient selection Between July 2007 and August 2011, 1,050 patients received liver resection at Asan Medical Centre for HCC. Among them, patients with single-lesion HCC (\5 cm) who never received liver resection, trans-arterial chemoembolization (TACE) and radiofrequency ablation (RFA) before surgery were selected for this study to exclude the influence of TACE and RFA. There were 318 cases of OLR and 74 cases of LLR. After performing a 3–1 propensity score-matched analysis, there were 174 cases of OLR and 58 cases of LLR. LLR has been carried out since July 2007 by a single experienced surgeon responsible for liver donor hepatectomy and hepato-biliary surgery over 10 years. OLRs were performed by a hepato-biliary team of extensive experienced surgeons with a standardized protocol. The indications for LLR were similar to indications for OLR. The main concerns of surgical indication were preoperative liver function and type of liver resection. Location of the tumor in a peripheral site or not was not a significant consideration. Whether LLR or not was dependent on the surgeon’s preference. Anatomical liver resection and functioning of the remnant liver were preferentially considered in both LLR and OLR. The localization of HCC was done by Couinaud’s classification. The patients undergoing LLR were compared to patients who underwent OLR with respect to preoperative, intraoperative, postoperative, and oncologic aspects. Surgical procedure Laparoscopic liver resection Laparoscopy was then performed under CO2 pneumoperitoneum. The patient was placed supine in the 30°D reversed Trendelenburg position, with the surgeon standing between the patient’s legs. Five trocars were usually
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inserted, with the middle trocar used for the main working device. Exploration of the extent of the tumor and determination of its relationship with the vascular anatomy and other tumors in the liver were performed using intraoperative ultrasonography. Liver traction was done by atraumatic graspers (Direct Drive laparoscopic grasper; Applied Medical Resources, Rancho Santa Margarita, California, USA). These instruments can help pull the liver atraumatically during division of the hepatic parenchyma. Transection of liver parenchyma was performed using Harmonic ScalpelTM (Ethicon Endosurgery, Cincinnati, Ohio, USA). The deep hepatic parenchyma was divided using a laparoscopic CUSA. During LLR, en masse or blind stapling of the hepatic parenchyma cannot be performed to achieve meticulous haemostasis and biliostasis. In 4 cases of right hepatectomy (RH) and 5 cases of right posterior segmentectomy (RPS), a ‘hanging-over’ maneuver was used, which results in easier, more accurate hepatectomy, and provides a better view of the hepatic veins and Glisson’s pedicles. The benefit of ‘hanging-over’ maneuver was better exposure and hemostasis of the deeper plane of parenchyma (Fig. 1A). Small branches of Glisson’s pedicles were clipped by metal clip, and large Glisson’s pedicles were ligated using a knot pusher (5 mm knot guide; MGB Endoscopy Corporation, Seoul, Korea) or endoscopic linear stapler (Echelon FlexTM; Ethicon Endosurgery, Cincinnati, USA) with 45 mm gold cartridge (Fig. 1B). After parenchymal dissection, endoscopic linear stapler (Echelon FlexTM; Ethicon Endosurgery, Cincinnati, USA) with 45 mm white cartridge was used to ligate the main hepatic veins (Fig. 1C). Once free, the specimen was placed in an endobag by insertion through a 12-mm trocar and retrieved through a 10-cm Pfannenstiel incision.
Statistical analysis We performed a 3–1 propensity score-matched analysis. Propensity scores were computed by modeling a logistic regression with the dependent variable as the odds of undergoing LLR, and the independent variables as age, sex, underlying liver disease, ICG, PT, and pathology. For statistical analysis, Two-way ANOVA test, Friedman test, Cochran-Mantel-Haenzel test, and Stratified log-rank test (for survival rates) were used. Data were summarized as frequencies and proportions, and differences between groups were evaluated by the Cochran-Mantel-Haenzel test for categorical variables or Two-way ANOVA and Friedman test for continuous variables. Statistical significance was set at P \ 0.05. SPSS version 20 (SPSS, Chicago, Illinois, USA) and SAS V9.3 were used for all statistical analyses.
Surg Endosc Table 1 Preoperative patient characteristic and laboratory findings OLR (n = 174)
LLR (n = 58)
55.0 (49–61)
54.3 (49–63)
Age Female/Male (Ratio)
44/130 (0.34)
Pa 0.64b 0.23c
13/45 (0.28)
0.71c
Liver disease HBV
165 (94.8 %)
HCV
6 (3.5 %)
54 (93.1 %) 3 (5.2 %)
Alcoholic hepatitis
3 (1.7 %)
1 (1.7 %)
ICG 15 (%) AFP level (ng/mL)
12.4 (8.9–15.2) 469 (3.2–200)
12.14 (8.6–14) 2553 (3.1–132)
Platelets 9 103/ mm3
153 (121–192)
152 (117–187)
0.68b 1.00 1.00
INR
1.05 (0.88–1.39)
1.07 (0.95–1.90)
0.50
Total Bilirubin (mg/dl)
1.02 (0.8–1.2)
1.06 (1.01–1.1)
0.06
Albumin (g/dL)
3.89 (3.7–4.2)
3.84 (3.6–4.1)
CTP score A B
0.13 0.72
158 (90.8 %) 16 (9.2 %)
53 (91.4 %) 5 (8.6 %)
Values are median (interquartile range) except gender ratio and liver disease OLR open liver resection, LLR laparoscopic liver resection, AST aspartate aminotransferase, ALT alanine aminotransferase, ICG 15 indocyanine green retention rate at 15 min a
Friedman test, except
b
Two-way ANOVA
c
Cochran-Mantel-Haenzel test
Comparison of the surgical parameters relating to the operation
Fig. 1 Procedures of laparoscopic liver resection. A ‘Hanging over’ maneuver, B Ligation of Glisson’s pedicles by Hem-o-lok and endoscopic linear stapler with 45 mm gold cartridge, C Hepatic vein cutting by endoscopic linear stapler with 45 mm white cartridge
Results Preoperative characteristics comparison of between OLR and LLR group Demographic data of the clinicopathological features in the OLR and LLR groups are shown in Table 1. There were no significant differences between the two groups in age, underlying disease, ICG, AFP, platelets, INR, bilirubin, and albumin. 158 patients of OLR and 53 patients of LLR were CTP grade A.
In the OLR group, 115 (66.1 %) were anatomical hepatectomy (more than 2 segments). These include 20 RH, 24 right anterior segmentectomy (RAS), 38 RPS, 13 left hepatectomy (LH), 6 central bisegmentectomy (CBS), and 8 left lateral segmentectomy (LLS). 43 (74.1 %) were anatomical hepatectomy (more than 2 segments) in the LLR group. These included 4 right hepatectomy (LRH), 5 right posterior segmentectomy (LRPS), 6 left hepatectomy (LLH), and 28 left lateral segmentectomy (LLLS). The mean duration of operation was 255 (200–300) mins in the OLR group and 207 (146–251) mins in the LLR group (P = 0.00). The transfusion rate was 13 (7.5 %) and 2 (3.4 %), respectively, and significantly high in OLR (P = 0.04). All LLRs were successful. There were no notable differences in operative times between the two groups, and there was no case of conversion to open surgery (Table 2, 3). Postoperatively, the patients started diet significantly earlier in the LLR group: 2.4 (1–4) days of postoperative fasting in the OLR group and 2.8 (1–5) days of
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Surg Endosc Table 2 Type of liver resection Type of liver resection
OLR (n = 174)
LLR (n = 58)
RH
20
RH
RAS
24
RPS
38
RPS
LH
13
LH
Table 3 Surgical outcomes of and oncologic finding by operative type LLR (n = 58)
Operation time (mins)a
255 (200–300)
207 (146–251)
0.00
5
Transfusion
13 (7.5 %)
2 (3.4 %)
0.04d
6
2.8 (1–5) 15 (8–22)
2.4 (1–4) 9.2 (6–14)
0.01 0.00
4
LLS
8
LLS
28
Recovery to diet (days) Hospital day (days)
Partial hepatectomy
59
Partial hepactectomy
15
Complicationb
Central Bisegmentectomy
6
Open conversion
0
RH right hepatectomy, RAS right anterior segmentectomy, RPS right posterior segmentectomy, LH left hepatectomy, LLS left lateral segmentectomy
postoperative fasting in the LLR group (P = 0.01), and the patients of LLR recovered more rapidly, which consequently resulted in shorter hospitalization: 15 (8–22) days in the OLR group and 9.2 (6–14) days in the LLR group (P = 0.00). The resumption of diet was determined by recovery of bowel sound and normalization of bowel gas distribution on simple abdominal X-ray. The criteria of discharge were composed of dietary recovery, normalization of laboratory findings, and no surgical complication. The LLR group had a 6.9 % complication rate, and the OLR group had a complication rate of 22.4 % (P = 0.02). Grade I and II complication (Clivein–Dindo) was 32 and 3 in the OLR group and 3 and 1 in the LLR group, respectively (P = 0.02). Significant postoperative complications (IIIa) occurred in 3 cases of OLR and 1 case of LLR. A bile leak requiring interventional drainage or stent placement was the most common complication (n = 4; OLR, n = 1; LLR). Bleeding requiring interventional embolization was one case in OLR. Severe postoperative complication requiring operation (IIIb) occurred in 1 case of OLR. (Table 3). Comparison of the treatment outcomes in oncologic aspect between LLR and OLR group Recurrences related to laparoscopy, such as peritoneal dissemination and port-site recurrences, were not observed in the LLR group. To investigate the oncologic outcomes between the laparoscopic and open group, the authors compared data on surgical margin, margin-positive rate, and tumor recurrence. On the pathologic aspect, there were significant differences in the safety resection margin between the two groups: 1.12 (0.3–2.0) cm in the OLR
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Pc
OLR (n = 174)
0.02d
I
32
3
II
3
1
IIIa
3
1
IIIb
2
None
Descriptions of complication I
Wound infection (32)
Wound infection (3)
II
Intra-abdominal fluid collection (1) Bile leakage (2)
Bile leakage (1)
IIIa
Bile leakage (2) Bleeding (1) Bleeding (2)
Bile leakage (1) None
3 (1.7 %)
0 (0.0 %)
1.12 (0.3–2.0)
2.03 (0.8–3.0)
0.01
3.04 (0.20–4.9)
2.87 (0.70–4.9)
0.23
IIIb Resection margin (?) Resection margin (cm)
a
Tumor size (cm)
0.03d
Recurrence (%)
31 (17.8 %)
16 (27.6 %)
0.10
Edmonson–Steiner grade
OLR (n = 174)
LLR (n = 58)
0.25
I II
6 (3.4 %) 40 (23.0 %)
3 (5.2 %) 19 (32.8 %)
III
79 (45.4 %)
29 (50.0 %)
IV
33 (19.0 %)
3 (5.2 %)
16 (9.2 %)
4 (6.8 %)
Lymphovascular invasion
4 (2.3 %)
4 (6.9 %)
0.62
Capsular invasion
11 (6.3 %)
5 (8.6 %)
0.41
Necrotic nodule Microinvasion
Values are median (range), except operation time and resection margin (cm) a
Values are median (interquartile range)
b
Complication was categorized by Clavien–Dindo classification
c
Friedman test, except
d
Cochran-Mantel-Haenzel test
group and 2.03 (0.8–3.0) cm in the LLR group (P = 0.01). There were 3 cases (1.7 %) of resection margin involvement in the OLR group in contrast to no cases in the LLR group (P = 0.03). There was also no significant difference
Surg Endosc
in recurrence of HCC between the two groups: 31 cases (17.8 %) in the OLR group and 16 cases (27.6 %) in the LLR group (P = 0.10). With regard to the pathologic aspect, the most common Edmonson-Steiner grade was III in both groups. Grade II and III were 40 (23.0 %) and 79 (45.4 %) in the OLR group and 19 (32.8 %) and 29 (50.0 %) in the LLR group, respectively (P = 0.25). The 1-, 2-, 3-, and 4-year overall survival rates for the ORL and LLR groups were 98.0, 93.0, 84.0, and 68 % and 95.0, 92.0, 86.0, and 86.0 %, respectively (Fig. 2, P = 0.48). The 1-, 2-, 3- and 4-year disease-free survival rates for the ORL and LLR groups were 88.0, 79.0, 62.0, and 62.0 % and 82.0, 63.0, 56.0, and 56.0 %, respectively (Fig. 3, P = 0.31). Thus, there was no significant difference between the two groups in overall and disease-free survival at 1-, 2-, 3-, and 4-years, respectively.
Discussion On this study, more objective and adequate comparative analysis with the two groups (LLR and OLR) could be deduced. This is probably because the OLR could only be carried out by surgical teams with expertise in liver surgery and liver transplantation under the standardized protocol and with standardized methods [7]. In the authors’
Fig. 2 4-year overall survival for the two groups The 4-year overall survival rates for ORL and LLR groups were 68.0 and 86.0 %, respectively (P = 0.48). There were no statistically significant differences between LLR and OLR in the overall survival during 4 years
Fig. 3 4-year disease-free survival for the two groups The 4-year disease-free survival rates for ORL and LLR groups were 62.0 and 56.0 %, respectively (P = 0.31). There were no statistically significant differences between LLR and OLR in the disease-free survival during 4 years
institution, more than 700 OLR, 300 living donor liver transplantations (LDLT), and 35 LLR are done annually. This study shows conclusively that LLR appears to be comparable or superior to OLR regardless of the location of the tumor. The LLR group had not only a better cosmetic effect, but also had a comparable result on oncologic aspect. With regard to anatomical hepatectomy, anatomical hepatectomy of more than 2 segments was 115 (66.1 %) in the OLR group and 43 (74.1 %) in the LLR group. In other studies, most cases in the laparoscopic group were segmentectomies or subsegmentectomies located in segments II, III, IV, VI, or VI. Also, tumor size, type, and location are important in determining indications for LLR for HCC [8–11]. It has been reported that HCC with small size (5 \ cm) located in superficial and peripheral sites could be an indication for LLR. But, several retrospective studies have shown that the survival rate of patients operated on by anatomical resection was superior to that of patients operated on by non-anatomical resection, according to remnant function [12, 13]. In our institute, anatomical liver resection is preferred by the surgical team if the remnant liver function is tolerable. The laparoscopic surgeon also considers anatomical liver resection to be important in LLR. Intraoperative ultrasonography can help with the demarcation of segments and the identification of the tumor.
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As with many institutions, the conversion rate to open hepatectomy in our study was zero in LLR; in the literature, general conversion rates ranged between 0 and 20 % [14, 15]. Once the LLR plan for a patient was determined, operative decision making started with high-quality crosssectional 3D CT imaging according to the liver surgeon’s needs. In the case of LH or poor demarcation of the main mass, magnetic resonance imaging can help the surgeon understand the biliary anatomy and boundaries of the main mass. Therefore, good planning before an LLR operation can prevent conversion to open hepatectomy. Consistent with previous studies, the authors have seen less transfusion rate, shorter hospital stays, and fewer complications during the postoperative course with the laparoscopic approach, but controversial results in operation time [3, 16–19]. Advantages of LLR include decreased blood loss and transfusion rate. Intraoperative pneumoperitoneum and image magnification may help reduce blood loss and provide easier access to the hepatic vein and Glisson’s pedicles [20]. Blood loss has been showed to have a prejudicial impact on both short- and long-term outcomes. It has also been reported that perioperative transfusion is associated with poor prognosis [21–23]. Better integrity of the abdominal wall may be attributable to early discharge from hospital and to reduction of pain at the surgical site. Rapid recovery from surgery and an earlier discharge from the hospital provide further evidence for the safety and feasibility of LLR. Actually, some institutes including our institute have even performed LLR on liver graft retrieval for LDLT, the performance of which predicts the potentially enormous value of LLR in liver surgery [1, 24]. With the oncologic aspect, there were also no significant differences in tumor size, tumor pathologic grade, pathologic invasiveness, recurrence, 4-year survival, and eventual 4-year disease-free survival rate. Most series in the literature revealed no difference in resection margin involvement rate and distance from resection margin between LLR and OLR, but our study revealed a significant higher margin involvement and shorter distance from resection margin in the ORL group [25, 26]. This may be due to a patient selection bias because of choosing to perform OLR for tumors located close to hilum, inferior vena cava, or major hepatic veins. Although the lack of palpation in LLR may decrease the surgery margin, when an anatomic resection is planned and intraoperative ultrasound is used to locate the purposed margin and the tumor could also be achieved laparoscopically. Several studies in the literature reported the long-term result of laparoscopic hepatectomy for HCC. The reported 5-year overall survival of laparoscopic hepatectomy for HCC ranged from 50 to 75 %, and the 5-year disease-free survival ranged from 24 to 45.6 % [6, 14]. The 4-year
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overall and disease-free survival in the laparoscopic hepatectomy for HCC (\5 cm) in this study were 86.0 and 56.0 %, respectively. It is explained by restricted indication as HCC (\5 cm) without treatment history of TACE, RFA, or surgery. So, it must be noticed that the results were based on the selected patients of relative early stage of tumor in our study. The conclusions of this retrospective analysis are limited by several factors. More detailed longterm studies especially in the form of RCTs will be needed to confirm our conclusion. Despite improvement in surgical methods and medications to treat HCC over the past few decades, recurrence and metastasis are still frequently seen, and the 5-year survival rate of patients with HCC is still quite low [27, 28]. Resection is safer and superior to in loco-regional treatment. Especially, LLR can result in a smaller scar and reduced intraperitoneal adhesions. Therefore, LLR can facilitate reoperation for recurrent HCC and can be a life-prolonging bridge operation before transplantation [29]. But, laparoscopic major hepatectomy still remains a technically demanding procedure and should only be performed by experienced hepato-biliary surgeons with expertise in open liver section and laparoscopic surgery after adequate training [30]. Conclusively, LLR is a safe and feasible alternative for selected patients with HCC (\5 cm) and was shown not to increase the tumor recurrence risk or adversely affect oncologic outcomes. LLR is a safe and developing technique in a select group of patients with HCC. LLR has the advantages of rapid recovery and low morbidity with acceptable oncological and pathological parameters. It may be an optimal and promising method of hepatectomy in HCC (\5 cm). Longer follow-up periods are needed to make more definite conclusions about the comparative survival probability of the two groups (LLR and OLR).
Conflict of interest
The authors have no conflicts of interest.
Disclosures Sam-Youl Yoon, Ki-Hun Kim, Dong-Hwan Jung, Sung-Gyu Lee, and Ami Yu has no conflicts of interest or financial ties to disclose.
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