- Email: [email protected]
Long-Term Favorable Surgical Results of Laparoscopic Hepatic Resection for Hepatocellular Carcinoma in Patients with Cirrhosis: A Single-Center Experience over a 10-Year Period
Long-Term Favorable Surgical Results of Laparoscopic Hepatic Resection for Hepatocellular Carcinoma in Patients with Cirrhosis: A Single-Center Experience over a 10-Year Period Yo-ichi Yamashita, MD, PhD, Tetsuo Ikeda, MD, PhD, Takeshi Kurihara, MD, Yoshihiro Yoshida, Kazuki Takeishi, MD, PhD, Shinji Itoh, MD, PhD, Norifumi Harimoto, MD, PhD, Hirofumi Kawanaka, MD, PhD, Ken Shirabe, MD, PhD, Yoshihiko Maehara, MD, PhD, FACS
MD,
We first performed laparoscopic hepatic resection (Lap-Hx) for hepatocellular carcinoma (HCC) in 1994. Here we review the long-term surgical results of Lap-Hx for HCC in patients with cirrhosis over a 10-year period at a single institution. STUDY DESIGN: Between January 2000 and December 2013, 99 patients with cirrhosis underwent open hepatic resection (Open-Hx) and 63 underwent Lap-Hx for primary HCC within the Milan criteria. We compared the operative outcomes and patient survival between the 2 groups. RESULTS: There were no significant differences regarding patient background characteristics or tumorrelated factors between the 2 groups. The morbidity rate of the Lap-Hx group was significantly lower than that of the Open-Hx group (26% vs 10%; p ¼ 0.0459), and the complication rate of ascites was significantly lower (7% vs 0%; p ¼ 0.0077). The mean duration of hospital stay of the Lap-Hx group was significantly shorter than that of the OpenHx group (16 vs 10 days; p ¼ 0.0008). There were no significant between-group differences regarding overall or disease-free survival. CONCLUSIONS: Laparoscopic-Hx for HCC in patients with cirrhosis is associated with less morbidity and shorter hospital stays, with no compromise in patient survival. It may be time to consider changing the standard operation for primary HCC within the Milan criteria to Lap-Hx in patients with cirrhosis. (J Am Coll Surg 2014;219:1117e1123. 2014 by the American College of Surgeons)
BACKGROUND:
Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide, accounting for approximately 6% of all human cancers.1 The mainstay of curative treatment for HCC is hepatic resection, and the surgical results of hepatic resection for HCC have significantly improved, with the mortality rate nearly reaching zero.2 However, hepatic resection for HCC remains high risk, especially in patients with cirrhosis. As a less invasive procedure, laparoscopic hepatic resection Disclosure Information: Nothing to disclose. Received June 29, 2014; Revised August 26, 2014; Accepted September 2, 2014. From the Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. Correspondence address: Yo-ichi Yamashita, MD, PhD, Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. email: [email protected]
ª 2014 by the American College of Surgeons Published by Elsevier Inc.
(Lap-Hx) for HCC has gathered attention in this challenging field.3 We first performed Lap-Hx for HCC in patients with cirrhosis in 1994.4 Until 2007, we selected Lap-Hx for HCC on the left lateral lobe or the peripheral ventral right lobe, and we performed liver parenchymal division through a small laparotomy after mobilization of the liver. We reported favorable short-term surgical results of LapHx for HCC, with less blood loss and shorter hospital stays, with no compromise in patient survival.5 In June 2008, pure Lap-Hx was introduced in our institution,6 and Lap-Hx for the posterior segment, anterosuperior segment (S8), and caudate lobe was performed with the patient in the semiprone position.7,8 Several meta-analyses summarized the surgical results of Lap-Hx for HCC as follows: less blood loss, less frequent need for transfusion, less morbidity, a lower complication rate of ascites, a lower complication rate of liver failure,
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Abbreviations and Acronyms
HCC Lap Hx ICGR-15 Open-Hx
¼ ¼ ¼ ¼
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hepatocellular carcinoma laparoscopic hepatic resection indocyanine green retention rate at 15 minutes open hepatic resection
shorter hospital stays, and no compromise in prognosis. 9-13 However, long-term (ie, more than 10 years) surgical results of Lap-Hx for HCC in patients with cirrhosis have not yet been reported. We herein present a retrospective analysis of long-term surgical results including patients’ prognoses after Lap-Hx for HCC within the Milan criteria14 (ie, 5 cm in diameter in single HCC or 3 nodules and 3 cm in diameter in multiple HCCs) in patients with cirrhosis, over a 10year period at a single institution.
METHODS Patient characteristics We retrospectively analyzed 653 patients with HCC who underwent hepatic resections at the Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, from January 2000 to December 2013. Among them, 162 patients who underwent curative hepatic resections for primary HCC within the Milan criteria were enrolled in this study. We divided this cohort of 162 patients into 2 groups; the open hepatic resection (Open-Hx) group (n ¼ 99), and the Lap-Hx group (n ¼ 63).
for the posterior segment, anterosuperior segment (S8), and caudate lobe was performed with the patient in the semiprone position.7,8 In patients who underwent the Lap-Hx, bipolar scissors or a Biclamp under the VIO soft-coagulation system (ERBE Elektromedizin) fitted with a silicon tube dropping saline to the tip was used to transect the liver parenchyma. If transection of the liver parenchyma of S7, S8, or the right superior portion of S1 was needed in the Lap-Hx patients, an intracostal port with a balloon was placed under left-lung ventilation.8 Types of hepatic resections in both the Open-Hx group and the Lap-Hx group are summarized in Table 1. There were no patients who underwent lobectomy or more for HCC within the Milan criteria in our series. The majority of operations performed were partial hepatic resections: 71 patients (71.7%) in the Open-Hx group and 36 patients (57.1%) in the Lap-Hx group. Any death that occurred in the hospital after hepatic resection was recorded as a mortality. Complications were evaluated by Clavien’s classification of surgical complications, and the complications with a score of grade II or more were defined as positive.18 Follow-up and treatment strategy for recurrent hepatocellular carcinoma After discharge, all patients were examined for recurrence by ultrasonography and tumor markers such as a-fetoprotein (AFP) and des-g-carboxy prothrombin (DCP) every month and by dynamic CT every 3 Table 1. Types of Hepatic Resection
Surgical procedures and outcomes Details of our surgical techniques of Open-Hx and patient selection criteria for hepatic resection for HCC have been reported.15,16 Resection volume was decided based on the patients’ indocyanine green dye retention rate at 15 minutes (ICGR-15) in both the Open-Hx and Lap-Hx groups. Patients with an ICGR-15 35% were generally selected for limited resection.16 From 1994 to 2007 in 25 patients (40%), Lap-Hx was done on the principle that parenchymal division would be performed under direct vision through a small laparotomy wound after mobilization of the liver under a carbon dioxide (CO2) pneumoperitoneum. The CUSA system (Valleylab) was used to transect the liver parenchyma. In almost all of the hepatic resections, the Pringle’s maneuver, consisting of clamping the portal triad for 15 minutes and then releasing the clamp at 5-minute intervals, was applied; alternatively, hemivascular occlusion17 was performed. From June 2008 in 38 patients (60%), pure Lap-Hx was introduced in our institution,6 and Lap-Hx
Operative procedures
Lobectomy or more Right liver Left liver Segmentectomy or more Left lateral Medial Anterior Posterior Subsegmentectomy or more* S2 S3 S5 S6 S7 S8 S5 þ 6 Partials
Open (n ¼ 99)
Laparoscopic (n ¼ 63)
0 0
0 0
4 3 1 1
13 1 0 5
0 2 4 7 2 3 1 71
2 1 1 2 0 1 1 36
*S, segment defined by the Couinaud’s nomenclature.
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Table 2.
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Comparisons of Patient Background Characteristics
Variables
Age Male/female, n DM (þ), n (%) HBs-Ag (þ), n (%) HCV-Ab (þ), n (%) Alb, g/dL, mean SD T-bil, mg/dL, mean SD ICGR-15, %, mean SD Child A/B, n Liver damage A/B, n
Open (n ¼ 99)
Laparoscopic (n ¼ 63)
p Value
65.2 10.1 74/25 24 (24) 17 (17) 68 (68) 3.99 0.38 0.82 0.32 16.1 8.1 96/3 76/23
67.5 9.5 48/15 20 (32) 10 (16) 40 (63) 3.93 0.40 0.86 0.39 16.3 8.3 59/4 44/19
0.1483 0.8353 0.2977 0.3813 0.4952 0.3266 0.1263 0.9059 0.3187 0.3293
Alb, albumin; DM, diabetes mellitus; HBs-Ag, hepatitis B surface antigen; HCV-Ab, hepatitis C virus antibody; ICGR15, indocyanin green retention rate at 15 min; T-bil, total bilirubin.
months.16 The mean follow-up period after hepatic resection was 4.2 years (range 0.3 to 13.7 years) in the OpenHx group, and 3.4 years (range 0.2 to 13.4 years) in the Lap-Hx group. When recurrence was suspected, we treated the recurrent HCC by repeat hepatic resection at any times of recurrence,19 with ablation therapy or liodolization.20 Statistics Continuous variables are expressed as the mean standard deviation (SD) and were compared using Student’s t-test. Categorical variables were compared using the chi-square test. Survival curves were generated by the Kaplan-Meier method and compared using the log-rank test. All analyses were performed with JMP Pro 9.0.2 (SAS Institute Inc). Values of p < 0.05 were considered significant.
RESULTS Patients’ background characteristics The patients’ background characteristics are summarized in Table 2. There are no significant differences in the patient characteristics between the Open-Hx and the LapHx groups, including mean age (65.2 vs 67.5 years; p ¼ 0.1483), the positive rate of diabetes mellitus (24% vs 32%; p ¼ 0.2977), hepatitis B surface antigen (17% vs 16%; p ¼ 0.3813), and hepatitis C virus antibody (68% vs 63%; p ¼ 0.4952), respectively. Concerning liver function, such as the serum level of albumin (3.99 vs 3.93 g/dL; p ¼ 0.3266) and total bilirubin (0.82 vs 0.86 mg/dL; p ¼ 0.1263), ICGR-15 (16.1% vs 16.3%; p ¼ 0.9059), the ratio of Child A/B (96/3 vs 59/4; p ¼ 0.3187) and Liver damage A/B (76/23 vs 44/19; p ¼ 0.3293), respectively, there were also no significant differences between the 2 groups.
Short-term surgical outcomes The patients’ short-term surgical outcomes are summarized in Table 3. The mean resected liver volume in the Lap-Hx group (112.2 97.3 g) was significantly larger than that in the Open-Hx group (81.2 65.3 g; p ¼ 0.0165). There were no deaths in either group, and the morbidity rate in the Lap-Hx group (10%) was significantly lower than that in the Open-Hx group (26%; p ¼ 0.0459). Concerning the breakdown of morbidity, the positive rate of ascites in the Lap-Hx group (0%) was significantly lower than that in the Open-Hx group (7%; p ¼ 0.0077). The duration of hospital stay in the Lap-Hx group (10.3 4.4 days) was significantly shorter than that in the Open-Hx group (16.2 13.4 days; p ¼ 0.0008). Tumor-related factors Tumor-related factors are summarized in Table 4. There were no significant differences in tumor-related factors between the 2 groups, including the maximum tumor diameter (2.6 vs 2.5 cm; p ¼ 0.5106), the positive rate of solitary tumor (84% vs 89%; p ¼ 0.4593), poorly differentiated HCC (20% vs 19%; p ¼ 0.8570), pathologic portal vein infiltration and/or intrahepatic metastasis (27% vs 19%; p ¼ 0.4952), and stages III/IV-A (13% vs 10%; p ¼ 0.4814), respectively. There were also no significant differences between the 2 groups regarding the tumor markers: serum levels of AFP (262.5 vs 593.4 ng/mL; p ¼ 0.3128) and DCP (183.3 vs 127.1 mAU/mL; p ¼ 0.1831), respectively. Survival after hepatic resections for hepatocellular carcinoma Disease-free survival and overall survival curves are provided in Figure 1. There were no significant differences in disease-free survival (p ¼ 0.5196) or overall survival
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Table 3.
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Comparisons of Short-Term Surgical Outcomes
Variables
Surgical outcomes Operation time, min, mean SD Blood loss, g, mean SD Transfusion, n (%) Resected liver volume, g, mean SD Anatomic resection, n (%) Surgical margin, mm, mean SD Postoperative courses Mortality, n (%) Morbidity, n (%) Bile leakage, n (%) Ascites, n (%) Surgical site infection, n (%) Hospital stay, d, mean SD
Open (n ¼ 99)
Laparoscopic (n ¼ 63)
p Value
287.4 83.2 436.6 320.7 2 (2) 81.2 65.3 28 (28) 5.8 6.9
299.5 127.6 455.7 741.9 4 (6) 112.2 97.3 27 (43) 7.4 8.7
0.4664 0.8221 0.1612 0.0165 0.0516 0.2243
0 (0) 26 (26) 2 (2) 7 (7) 9 (9) 16.2 13.4
(p ¼ 0.6791) between the 2 groups. The 2-year and 5year disease-free survival rates were 70% and 41% in the Open-Hx group, and 68% and 33% in the Lap-Hx group, respectively. The 5-year and10-year overall survival rates were 77% and 57% in the Open-Hx group, and 78% and 69% in the Lap-Hx group, respectively. There were no port site recurrences or peritoneal seeding of HCC in the Lap-Hx group.
DISCUSSION With advances and improvements in instruments and surgical experiences for laparoscopic surgery, there are increasing interests and options for Lap-Hx for HCC in patients with cirrhosis. The Louisville consensus statement concluded that laparoscopic left lateral sectionectomy should be considered standard practice, and it described the currently acceptable indications for LapHx as patients with a solitary lesion, 5 cm or less, located in liver segment 2e6.21 Several recent studies have reported their comparative results of Lap-Hx vs Open-Hx for HCC, and several meta-analyses summarized the Table 4.
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0 6 1 0 2 10.3
(0) (10) (2) (0) (3) 4.4
0.9999 0.0459 0.8405 0.0077 0.1249 0.0008
surgical and oncologic outcomes of Lap-Hx as follows: less blood loss, less frequent need for transfusion, less morbidity, a lower complication rate of ascites, a lower complication rate of liver failure, shorter hospital stays, and no compromise in prognosis.9-13 However, in our study, the intraoperative blood loss of the Lap-Hx group (455.7 741.9 g) did not significantly differ from that of the Open-Hx group (436.6 320.7 g; p ¼ 0.8221). Therefore, regarding the need for transfusion, there is no significant difference between the 2 groups (2% vs 6%; p ¼ 0.1612). High intraperitoneal pressure caused by CO2 pneumoperitoneum is considered to be one of the major reasons for reduced blood loss in Lap-Hx for HCC. However, generally speaking, Lap-Hx tends to be applied for limited resection to peripheral ventral small HCCs, in which hepatic resections are relatively easy to perform.9-13 These “selection biases” were one of the potential causes of the smaller blood loss in Lap-Hx for HCC in other studies.9,11-13 However, in our study, the resected liver volume of the Lap-Hx group (112.2 97.3 g) was significantly larger than that of the Open-Hx group (81.2 65.3 g; p ¼ 0.0165), and the
Comparisons of Tumor-Related Factors
Variables
Open (n ¼ 99)
Laparoscopic (n ¼ 63)
p Value
Maximum tumor diameter, cm Solitary tumor, n (%) Poorly differentiated HCC, n (%) VP and/or IM (þ), n (%) Stage III/IVA, n (%) AFP, ng/mL, mean SD DCP, mAU/mL, mean SD
2.6 1.1 84 (84) 20 (20) 27 (27) 13 (13) 262.5 131.6 183.3 534.5
2.5 1.0 56 (89) 12 (19) 12 (19) 6 (10) 593.4 205.3 127.1 208.9
0.5106 0.4593 0.8570 0.3356 0.4814 0.3128 0.1831
AFP, alpha-fetoprotein; DCP, des-gamma-carboxyprothrombin; IM, pathologic intrahepatic metastasis; VP, pathologic portal vein infiltration.
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Figure 1. (A) Disease-free survival and (B) overall survival curves after curative resection in cirrhotic patients with hepatocellular carcinoma who underwent open hepatic resection (OpenHX; n ¼ 99) or laparoscopic hepatic resection (Lap-Hx; n ¼ 63).
rate of anatomic resection was also higher (43% vs 28%; p ¼ 0.0516). Hepatic resections of segments 1, 7, and 8, where Lap-Hx is considered to be difficult to perform, reached up to 17 cases (27%) in our Lap-Hx group using the semiprone position.6-8 Therefore, the selection biases in HCC location indicated for Lap-Hx in our study would be smaller than those of the previous studies. Concerning short-term surgical results, also in our study, less Clavien II or more morbidity (26% vs 10%; p ¼ 0.0459), a lower complication rate of ascites (7% vs 0%; p ¼ 0.0077), and shorter hospital stays (16 vs 10 days; p ¼ 0.0008) of the Lap-Hx group were confirmed. The reduced morbidity of laparoscopic surgery in patients with cancer has been already reported in colorectal22 and gastric cancer,23,24 so laparoscopic procedures are regarded as “minimally invasive.” In addition, Lap-Hx for HCC in patients with cirrhosis should be minimally invasive compared with Open-Hx because there is less tissue destruction of the abdominal wall with small incisions and/or less mobilization and manipulation of the liver.3 A CO2 pneumoperitoneum is known to reduce local immune responses such as the secretion of tumor necrosis factor-a (TNF-a) or nuclear factor kappa-light-chainenhancer of activated B cells (NFkB) from peritoneal macrophages against surgical stress.25 Less destruction of intra-abdominal tissues and the favorable effects of a CO2 pneumoperitoneum in Lap-Hx would lead to a lower rate of postoperative ascites. The minimal invasiveness of Lap-Hx improves the postoperative quality of life and reduces surgical morbidities. In this study, we found that the duration of hospital stay in cirrhotic patients with HCC who underwent Lap-Hx was significantly shortened compared with that of the Open-Hx patients. Concerning patient prognoses, several meta-analyses reported that no compromise in prognosis was linked to the
Lap-Hx procedure.9-13 Our study is first to report the long-term (more than 10 years) favorable results of LapHx for HCC in patients with cirrhosis. The 5- and 10-year survival rates of cirrhotic HCC patients who underwent Lap-Hx were 78% and 69%, respectively. In addition, in laparoscopic surgery for colorectal and gastric cancers, no compromise in prognosis was found by a meta-analysis including several randomized control trials.23,26 Despite the comparable oncologic outcomes and some advantages of Lap-Hx for HCC, port-site recurrence has remained a concern.27 We routinely use the surgical porch to retract the resected liver specimen including the HCC from the port site in Lap-Hx, and we have had no patients with port site recurrences or related peritoneal seeding of HCC. The negative impact of surgical morbidity on the recurrence rate and long-term outcomes has been reported in patients with colorectal liver metastasis,28 colorectal cancer,29 gastric cancer,30 and esophageal cancer.31 Reduction of surgical morbidities such as postoperative ascites by the less invasiveness of Lap-Hx for HCC could lead to a survival impact for better prognosis after curative hepatic resection for HCC in patients with cirrhosis in further study. There have been no reported prospective randomized controlled studies of Lap-Hx vs Open-Hx for HCC, and only 1 trial is currently underway in Korea (www. ClinicalTrials.gov Identifier NCT00606385).32 To minimize the selection biases of Lap-Hx, a case-controlled study with propensity score matching for long-term outcomes of Lap-Hx for HCC was reported.33 However, in this study, there were originally no significant differences in the patients’ background characteristics, operation time, intraoperative blood loss, need for transfusion, or tumor-related factors that could affect the patient prognoses between the 2 groups. Based on our encouraging
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short-term and long-term results of Lap-Hx for primary HCC within the Milan criteria irrespective of the HCC location in patients with cirrhosis, well-conducted prospective randomized controlled trials with large numbers of patients are needed to confirm our favorable results. The next challenge of Lap-Hx for HCC should be against huge HCCs and laparoscopic re-resections. The feasibility and safety of Lap-Hx for HCC with a tumor size of 5 to 10 cm34 and laparoscopic re-resection for recurrent HCC35 have been reported, and we are now expanding the indication of Lap-Hx for repeat resections for recurrent HCC.
CONCLUSIONS In conclusion, Lap-Hx for HCC in patients with cirrhosis is associated with less morbidity and shorter hospital stays, with no compromise in patient survival. It may be time to consider changing the standard operation to Lap-Hx for primary HCC within the Milan criteria in patients with cirrhosis. Author Contributions Study conception and design: Yamashita, Ikeda, Kawanaka, Shirabe, Maehara Acquisition of data: Yamashita, Kurihara, Yoshida, Analysis and interpretation of data: Yamashita, Takeishi, Itoh, Harimoto Drafting of manuscript: Yamashita, Ikeda, Shirabe Critical revision: Maehara REFERENCES 1. Hassoun Z, Gores GJ. Treatment of hepatocellular carcinoma. Clin Gastroenterol Hepatol 2003;1:10e18. 2. Yamashita YI, Tsuijita E, Takeishi K, et al. Trends in surgical results of hepatic resection for hepatocellular carcinoma: 1,000 consecutive cases over 20 years in a single institution. Am J Surg 2014;207:890e896. 3. Shimada M, Harimoto N, Maehara S, et al. Minimally invasive hepatectomy: modulation of systemic reactions to operation or laparoscopic approach? Surgery 2002;131:S312e317. 4. Hashizume M, Takenaka K, Yanaga K, et al. Laparoscopic hepatic resection for hepatocellular carcinoma. Surg Endosc 1995;9:1289e1291. 5. Shimada M, Hashizume M, Maehara S, et al. Laparoscopic hepatectomy for hepatocellular carcinoma. Surg Endosc 2001;15:541e544. 6. Ikeda T, Yonemura Y, Ueda N, et al. Pure laparoscopic right hepatectomy in the semi-prone position using the intrahepatic Glissonian approach and a modified hanging maneuver to minimize intraoperative bleeding. Surg Today 2011;41: 1592e1598. 7. Ikeda T, Mano Y, Morita K, et al. Pure laparoscopic hepatectomy in semiprone position for right hepatic major resection. J Hepatobiliary Pancreat Sci 2013;20:145e150.
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8. Ikeda T, Toshima T, Harimoto N, et al. Laparoscopic liver resection in the semiprone position for tumors in the anterosuperior and posterior segments, using a novel dual-handling technique and bipolar irrigation system. Surg Endosc 2014; 28:2484e2492. 9. Yin Z, Fan X, Ye H, et al. Short- and long-term outcomes after laparoscopic and open hepatectomy for hepatocellular carcinoma: a global systematic review and meta-analysis. Ann Surg Oncol 2013;20:1203e1215. 10. Parks KR, Kuo YH, Davis JM, et al. Laparoscopic versus open liver resection: a meta-analysis of long-term outcome. HPB (Oxford) 2014;16:109e118. 11. Li N, Wu YR, Wu B, Lu MQ. Surgical and oncologic outcomes following laparoscopic versus open liver resection for hepatocellular carcinoma: A meta-analysis. Hepatol Res 2012;42:51e59. 12. Xiong JJ, Altaf K, Javed MA, et al. Meta-analysis of laparoscopic vs open liver resection for hepatocellular carcinoma. World J Gastroenterol 2012;18:6657e6668. 13. Zhou YM, Shao WY, Zhao YF, et al. Meta-analysis of laparoscopic versus open resection for hepatocellular carcinoma. Dig Dis Sci 2011;56:1937e1943. 14. Mazzaferro V, Regalia E, Doci R, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med 1996;334: 693e699. 15. Shimada M, Takenaka K, Fujiwara Y, et al. Risk factors linked to postoperative morbidity in patients with hepatocellular carcinoma. Br J Surg 1998;85:195e198. 16. Yamashita Y, Taketomi A, Itoh S, et al. Long-term favorable results of limited hepatic resections for patients with hepatocellular carcinoma: 20 Years of Experience. J Am Coll Surg 2007;205: 19e26. 17. Makuuchi M, Mori T, Gunve´n P, et al. Safety of hemihepatic vascular occlusion during resection of the liver. Surg Gynecol Obstet 1987;164:155e158. 18. Clavien PA, Barkun J, de Oliveira ML, et al. The ClavienDindo classification of surgical complications: five-year experience. Ann Surg 2009;250:187e196. 19. Yamashita Y, Shirabe K, Tsuijita E, et al. Third or more repeat hepatectomy for recurrent hepatocellular carcinoma. Surgery 2013;154:1038e1045. 20. Kanematsu T, Furuta T, Takenaka K, et al. A 5-year experience of lipiodolization: selective regional chemotherapy for 200 patients with hepatocellular carcinoma. Hepatology 1989;10:98e102. 21. Buell JF, Cherqui D, Geller DA, et al. World Consensus Conference on Laparoscopic Surgery. The international position on laparoscopic liver surgery: The Louisville Statement, 2008. Ann Surg 2009;250:825e830. 22. Yamamoto S, Inomata M, Katayama H, et al, for the Japan Clinical Oncology Group Colorectal Cancer Study Group. Short-term surgical outcomes from a randomized controlled trial to evaluate laparoscopic and open D3 dissection for stage II/III colon cancer: Japan Clinical Oncology Group Study JCOG 0404. Ann Surg 2014;260:23e30. 23. Cheng Q, Pang TC, Hollands MJ, et al. Systematic review and meta-analysis of laparoscopic versus open distal gastrectomy. J Gastrointest Surg 2014;18:1087e1099. 24. Wang W, Zhang X, Shen C, et al. Laparoscopic versus open total gastrectomy for gastric cancer: an updated meta-analysis. PLoS One 2014;9:e88753.
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25. BuunenM,GholghesaeiM,VeldkampR,etal.Stressresponsetolaparoscopicsurgery:areview.SurgEndosc2004;18:1022e1028. 26. Theophilus M, Platell C, Spilsbury K. Long-term survival following laparoscopic and open colectomy for colon cancer: a meta-analysis of randomized controlled trials. Colorectal Dis 2014;16:O75e81. 27. Chen YY, Yen HH. Subcutaneous metastases after laparoscopicassisted partial hepatectomy for hepatocellular carcinoma. Surg Laparosc Endosc Percutan Tech 2011;21:e41e43. 28. Ito H, Are C, Gonen M, et al. Effect of postoperative morbidity on long-term survival after hepatic resection for metastatic colorectal cancer. Ann Surg 2008;247:994e1002. 29. Law WL, Choi HK, Lee YM, Ho JW. The impact of postoperative complications on long-term outcomes following curative resection for colorectal cancer. Ann Surg Oncol 2007; 14:2559e2566. 30. Tokunaga M, Tanizawa Y, Bando E, et al. Poor survival rate in patients with postoperative intra-abdominal infectious complications following curative gastrectomy for gastric cancer. Ann Surg Oncol 2013;20:1575e1583.
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31. Lerut T, Moons J, Coosemans W, et al. Postoperative complications after transthoracic esophagectomy for cancer of the esophagus and gastroesophageal junction are correlated with early cancer recurrence: role of systematic grading of complications using the modified Clavien classification. Ann Surg 2009; 250:798e807. 32. Han H-S. Prospective randomized trial of laparoscopic versus open liver resection with hepatocellular carcinoma. Available at: http://clinicaltrials.gov/ct2/show/NCT00606385. Accessed September 15, 2014. 33. Kim H, Suh KS, Lee KW, et al. Long-term outcome of laparoscopic versus open liver resection for hepatocellular carcinoma: a case-controlled study with propensity score matching. Surg Endosc 2014;28:950e960. 34. Ai JH, Li JW, Chen J, et al. Feasibility and safety of laparoscopic liver resection for hepatocellular carcinoma with a tumor size of 5-10 cm. PLoS One 2013;21:e72328. 35. Chan AC, Poon RT, Chok KS, et al. Feasibility of laparoscopic re-resection for patients with recurrent hepatocellular carcinoma. World J Surg 2014;38:1141e1146.
MD,
We first performed laparoscopic hepatic resection (Lap-Hx) for hepatocellular carcinoma (HCC) in 1994. Here we review the long-term surgical results of Lap-Hx for HCC in patients with cirrhosis over a 10-year period at a single institution. STUDY DESIGN: Between January 2000 and December 2013, 99 patients with cirrhosis underwent open hepatic resection (Open-Hx) and 63 underwent Lap-Hx for primary HCC within the Milan criteria. We compared the operative outcomes and patient survival between the 2 groups. RESULTS: There were no significant differences regarding patient background characteristics or tumorrelated factors between the 2 groups. The morbidity rate of the Lap-Hx group was significantly lower than that of the Open-Hx group (26% vs 10%; p ¼ 0.0459), and the complication rate of ascites was significantly lower (7% vs 0%; p ¼ 0.0077). The mean duration of hospital stay of the Lap-Hx group was significantly shorter than that of the OpenHx group (16 vs 10 days; p ¼ 0.0008). There were no significant between-group differences regarding overall or disease-free survival. CONCLUSIONS: Laparoscopic-Hx for HCC in patients with cirrhosis is associated with less morbidity and shorter hospital stays, with no compromise in patient survival. It may be time to consider changing the standard operation for primary HCC within the Milan criteria to Lap-Hx in patients with cirrhosis. (J Am Coll Surg 2014;219:1117e1123. 2014 by the American College of Surgeons)
BACKGROUND:
Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide, accounting for approximately 6% of all human cancers.1 The mainstay of curative treatment for HCC is hepatic resection, and the surgical results of hepatic resection for HCC have significantly improved, with the mortality rate nearly reaching zero.2 However, hepatic resection for HCC remains high risk, especially in patients with cirrhosis. As a less invasive procedure, laparoscopic hepatic resection Disclosure Information: Nothing to disclose. Received June 29, 2014; Revised August 26, 2014; Accepted September 2, 2014. From the Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. Correspondence address: Yo-ichi Yamashita, MD, PhD, Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. email: [email protected]
ª 2014 by the American College of Surgeons Published by Elsevier Inc.
(Lap-Hx) for HCC has gathered attention in this challenging field.3 We first performed Lap-Hx for HCC in patients with cirrhosis in 1994.4 Until 2007, we selected Lap-Hx for HCC on the left lateral lobe or the peripheral ventral right lobe, and we performed liver parenchymal division through a small laparotomy after mobilization of the liver. We reported favorable short-term surgical results of LapHx for HCC, with less blood loss and shorter hospital stays, with no compromise in patient survival.5 In June 2008, pure Lap-Hx was introduced in our institution,6 and Lap-Hx for the posterior segment, anterosuperior segment (S8), and caudate lobe was performed with the patient in the semiprone position.7,8 Several meta-analyses summarized the surgical results of Lap-Hx for HCC as follows: less blood loss, less frequent need for transfusion, less morbidity, a lower complication rate of ascites, a lower complication rate of liver failure,
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http://dx.doi.org/10.1016/j.jamcollsurg.2014.09.003 ISSN 1072-7515/14
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Abbreviations and Acronyms
HCC Lap Hx ICGR-15 Open-Hx
¼ ¼ ¼ ¼
J Am Coll Surg
Surgical Results of Laparoscopic Hepatic Resection
hepatocellular carcinoma laparoscopic hepatic resection indocyanine green retention rate at 15 minutes open hepatic resection
shorter hospital stays, and no compromise in prognosis. 9-13 However, long-term (ie, more than 10 years) surgical results of Lap-Hx for HCC in patients with cirrhosis have not yet been reported. We herein present a retrospective analysis of long-term surgical results including patients’ prognoses after Lap-Hx for HCC within the Milan criteria14 (ie, 5 cm in diameter in single HCC or 3 nodules and 3 cm in diameter in multiple HCCs) in patients with cirrhosis, over a 10year period at a single institution.
METHODS Patient characteristics We retrospectively analyzed 653 patients with HCC who underwent hepatic resections at the Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, from January 2000 to December 2013. Among them, 162 patients who underwent curative hepatic resections for primary HCC within the Milan criteria were enrolled in this study. We divided this cohort of 162 patients into 2 groups; the open hepatic resection (Open-Hx) group (n ¼ 99), and the Lap-Hx group (n ¼ 63).
for the posterior segment, anterosuperior segment (S8), and caudate lobe was performed with the patient in the semiprone position.7,8 In patients who underwent the Lap-Hx, bipolar scissors or a Biclamp under the VIO soft-coagulation system (ERBE Elektromedizin) fitted with a silicon tube dropping saline to the tip was used to transect the liver parenchyma. If transection of the liver parenchyma of S7, S8, or the right superior portion of S1 was needed in the Lap-Hx patients, an intracostal port with a balloon was placed under left-lung ventilation.8 Types of hepatic resections in both the Open-Hx group and the Lap-Hx group are summarized in Table 1. There were no patients who underwent lobectomy or more for HCC within the Milan criteria in our series. The majority of operations performed were partial hepatic resections: 71 patients (71.7%) in the Open-Hx group and 36 patients (57.1%) in the Lap-Hx group. Any death that occurred in the hospital after hepatic resection was recorded as a mortality. Complications were evaluated by Clavien’s classification of surgical complications, and the complications with a score of grade II or more were defined as positive.18 Follow-up and treatment strategy for recurrent hepatocellular carcinoma After discharge, all patients were examined for recurrence by ultrasonography and tumor markers such as a-fetoprotein (AFP) and des-g-carboxy prothrombin (DCP) every month and by dynamic CT every 3 Table 1. Types of Hepatic Resection
Surgical procedures and outcomes Details of our surgical techniques of Open-Hx and patient selection criteria for hepatic resection for HCC have been reported.15,16 Resection volume was decided based on the patients’ indocyanine green dye retention rate at 15 minutes (ICGR-15) in both the Open-Hx and Lap-Hx groups. Patients with an ICGR-15 35% were generally selected for limited resection.16 From 1994 to 2007 in 25 patients (40%), Lap-Hx was done on the principle that parenchymal division would be performed under direct vision through a small laparotomy wound after mobilization of the liver under a carbon dioxide (CO2) pneumoperitoneum. The CUSA system (Valleylab) was used to transect the liver parenchyma. In almost all of the hepatic resections, the Pringle’s maneuver, consisting of clamping the portal triad for 15 minutes and then releasing the clamp at 5-minute intervals, was applied; alternatively, hemivascular occlusion17 was performed. From June 2008 in 38 patients (60%), pure Lap-Hx was introduced in our institution,6 and Lap-Hx
Operative procedures
Lobectomy or more Right liver Left liver Segmentectomy or more Left lateral Medial Anterior Posterior Subsegmentectomy or more* S2 S3 S5 S6 S7 S8 S5 þ 6 Partials
Open (n ¼ 99)
Laparoscopic (n ¼ 63)
0 0
0 0
4 3 1 1
13 1 0 5
0 2 4 7 2 3 1 71
2 1 1 2 0 1 1 36
*S, segment defined by the Couinaud’s nomenclature.
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Table 2.
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Comparisons of Patient Background Characteristics
Variables
Age Male/female, n DM (þ), n (%) HBs-Ag (þ), n (%) HCV-Ab (þ), n (%) Alb, g/dL, mean SD T-bil, mg/dL, mean SD ICGR-15, %, mean SD Child A/B, n Liver damage A/B, n
Open (n ¼ 99)
Laparoscopic (n ¼ 63)
p Value
65.2 10.1 74/25 24 (24) 17 (17) 68 (68) 3.99 0.38 0.82 0.32 16.1 8.1 96/3 76/23
67.5 9.5 48/15 20 (32) 10 (16) 40 (63) 3.93 0.40 0.86 0.39 16.3 8.3 59/4 44/19
0.1483 0.8353 0.2977 0.3813 0.4952 0.3266 0.1263 0.9059 0.3187 0.3293
Alb, albumin; DM, diabetes mellitus; HBs-Ag, hepatitis B surface antigen; HCV-Ab, hepatitis C virus antibody; ICGR15, indocyanin green retention rate at 15 min; T-bil, total bilirubin.
months.16 The mean follow-up period after hepatic resection was 4.2 years (range 0.3 to 13.7 years) in the OpenHx group, and 3.4 years (range 0.2 to 13.4 years) in the Lap-Hx group. When recurrence was suspected, we treated the recurrent HCC by repeat hepatic resection at any times of recurrence,19 with ablation therapy or liodolization.20 Statistics Continuous variables are expressed as the mean standard deviation (SD) and were compared using Student’s t-test. Categorical variables were compared using the chi-square test. Survival curves were generated by the Kaplan-Meier method and compared using the log-rank test. All analyses were performed with JMP Pro 9.0.2 (SAS Institute Inc). Values of p < 0.05 were considered significant.
RESULTS Patients’ background characteristics The patients’ background characteristics are summarized in Table 2. There are no significant differences in the patient characteristics between the Open-Hx and the LapHx groups, including mean age (65.2 vs 67.5 years; p ¼ 0.1483), the positive rate of diabetes mellitus (24% vs 32%; p ¼ 0.2977), hepatitis B surface antigen (17% vs 16%; p ¼ 0.3813), and hepatitis C virus antibody (68% vs 63%; p ¼ 0.4952), respectively. Concerning liver function, such as the serum level of albumin (3.99 vs 3.93 g/dL; p ¼ 0.3266) and total bilirubin (0.82 vs 0.86 mg/dL; p ¼ 0.1263), ICGR-15 (16.1% vs 16.3%; p ¼ 0.9059), the ratio of Child A/B (96/3 vs 59/4; p ¼ 0.3187) and Liver damage A/B (76/23 vs 44/19; p ¼ 0.3293), respectively, there were also no significant differences between the 2 groups.
Short-term surgical outcomes The patients’ short-term surgical outcomes are summarized in Table 3. The mean resected liver volume in the Lap-Hx group (112.2 97.3 g) was significantly larger than that in the Open-Hx group (81.2 65.3 g; p ¼ 0.0165). There were no deaths in either group, and the morbidity rate in the Lap-Hx group (10%) was significantly lower than that in the Open-Hx group (26%; p ¼ 0.0459). Concerning the breakdown of morbidity, the positive rate of ascites in the Lap-Hx group (0%) was significantly lower than that in the Open-Hx group (7%; p ¼ 0.0077). The duration of hospital stay in the Lap-Hx group (10.3 4.4 days) was significantly shorter than that in the Open-Hx group (16.2 13.4 days; p ¼ 0.0008). Tumor-related factors Tumor-related factors are summarized in Table 4. There were no significant differences in tumor-related factors between the 2 groups, including the maximum tumor diameter (2.6 vs 2.5 cm; p ¼ 0.5106), the positive rate of solitary tumor (84% vs 89%; p ¼ 0.4593), poorly differentiated HCC (20% vs 19%; p ¼ 0.8570), pathologic portal vein infiltration and/or intrahepatic metastasis (27% vs 19%; p ¼ 0.4952), and stages III/IV-A (13% vs 10%; p ¼ 0.4814), respectively. There were also no significant differences between the 2 groups regarding the tumor markers: serum levels of AFP (262.5 vs 593.4 ng/mL; p ¼ 0.3128) and DCP (183.3 vs 127.1 mAU/mL; p ¼ 0.1831), respectively. Survival after hepatic resections for hepatocellular carcinoma Disease-free survival and overall survival curves are provided in Figure 1. There were no significant differences in disease-free survival (p ¼ 0.5196) or overall survival
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Table 3.
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Comparisons of Short-Term Surgical Outcomes
Variables
Surgical outcomes Operation time, min, mean SD Blood loss, g, mean SD Transfusion, n (%) Resected liver volume, g, mean SD Anatomic resection, n (%) Surgical margin, mm, mean SD Postoperative courses Mortality, n (%) Morbidity, n (%) Bile leakage, n (%) Ascites, n (%) Surgical site infection, n (%) Hospital stay, d, mean SD
Open (n ¼ 99)
Laparoscopic (n ¼ 63)
p Value
287.4 83.2 436.6 320.7 2 (2) 81.2 65.3 28 (28) 5.8 6.9
299.5 127.6 455.7 741.9 4 (6) 112.2 97.3 27 (43) 7.4 8.7
0.4664 0.8221 0.1612 0.0165 0.0516 0.2243
0 (0) 26 (26) 2 (2) 7 (7) 9 (9) 16.2 13.4
(p ¼ 0.6791) between the 2 groups. The 2-year and 5year disease-free survival rates were 70% and 41% in the Open-Hx group, and 68% and 33% in the Lap-Hx group, respectively. The 5-year and10-year overall survival rates were 77% and 57% in the Open-Hx group, and 78% and 69% in the Lap-Hx group, respectively. There were no port site recurrences or peritoneal seeding of HCC in the Lap-Hx group.
DISCUSSION With advances and improvements in instruments and surgical experiences for laparoscopic surgery, there are increasing interests and options for Lap-Hx for HCC in patients with cirrhosis. The Louisville consensus statement concluded that laparoscopic left lateral sectionectomy should be considered standard practice, and it described the currently acceptable indications for LapHx as patients with a solitary lesion, 5 cm or less, located in liver segment 2e6.21 Several recent studies have reported their comparative results of Lap-Hx vs Open-Hx for HCC, and several meta-analyses summarized the Table 4.
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Surgical Results of Laparoscopic Hepatic Resection
0 6 1 0 2 10.3
(0) (10) (2) (0) (3) 4.4
0.9999 0.0459 0.8405 0.0077 0.1249 0.0008
surgical and oncologic outcomes of Lap-Hx as follows: less blood loss, less frequent need for transfusion, less morbidity, a lower complication rate of ascites, a lower complication rate of liver failure, shorter hospital stays, and no compromise in prognosis.9-13 However, in our study, the intraoperative blood loss of the Lap-Hx group (455.7 741.9 g) did not significantly differ from that of the Open-Hx group (436.6 320.7 g; p ¼ 0.8221). Therefore, regarding the need for transfusion, there is no significant difference between the 2 groups (2% vs 6%; p ¼ 0.1612). High intraperitoneal pressure caused by CO2 pneumoperitoneum is considered to be one of the major reasons for reduced blood loss in Lap-Hx for HCC. However, generally speaking, Lap-Hx tends to be applied for limited resection to peripheral ventral small HCCs, in which hepatic resections are relatively easy to perform.9-13 These “selection biases” were one of the potential causes of the smaller blood loss in Lap-Hx for HCC in other studies.9,11-13 However, in our study, the resected liver volume of the Lap-Hx group (112.2 97.3 g) was significantly larger than that of the Open-Hx group (81.2 65.3 g; p ¼ 0.0165), and the
Comparisons of Tumor-Related Factors
Variables
Open (n ¼ 99)
Laparoscopic (n ¼ 63)
p Value
Maximum tumor diameter, cm Solitary tumor, n (%) Poorly differentiated HCC, n (%) VP and/or IM (þ), n (%) Stage III/IVA, n (%) AFP, ng/mL, mean SD DCP, mAU/mL, mean SD
2.6 1.1 84 (84) 20 (20) 27 (27) 13 (13) 262.5 131.6 183.3 534.5
2.5 1.0 56 (89) 12 (19) 12 (19) 6 (10) 593.4 205.3 127.1 208.9
0.5106 0.4593 0.8570 0.3356 0.4814 0.3128 0.1831
AFP, alpha-fetoprotein; DCP, des-gamma-carboxyprothrombin; IM, pathologic intrahepatic metastasis; VP, pathologic portal vein infiltration.
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Figure 1. (A) Disease-free survival and (B) overall survival curves after curative resection in cirrhotic patients with hepatocellular carcinoma who underwent open hepatic resection (OpenHX; n ¼ 99) or laparoscopic hepatic resection (Lap-Hx; n ¼ 63).
rate of anatomic resection was also higher (43% vs 28%; p ¼ 0.0516). Hepatic resections of segments 1, 7, and 8, where Lap-Hx is considered to be difficult to perform, reached up to 17 cases (27%) in our Lap-Hx group using the semiprone position.6-8 Therefore, the selection biases in HCC location indicated for Lap-Hx in our study would be smaller than those of the previous studies. Concerning short-term surgical results, also in our study, less Clavien II or more morbidity (26% vs 10%; p ¼ 0.0459), a lower complication rate of ascites (7% vs 0%; p ¼ 0.0077), and shorter hospital stays (16 vs 10 days; p ¼ 0.0008) of the Lap-Hx group were confirmed. The reduced morbidity of laparoscopic surgery in patients with cancer has been already reported in colorectal22 and gastric cancer,23,24 so laparoscopic procedures are regarded as “minimally invasive.” In addition, Lap-Hx for HCC in patients with cirrhosis should be minimally invasive compared with Open-Hx because there is less tissue destruction of the abdominal wall with small incisions and/or less mobilization and manipulation of the liver.3 A CO2 pneumoperitoneum is known to reduce local immune responses such as the secretion of tumor necrosis factor-a (TNF-a) or nuclear factor kappa-light-chainenhancer of activated B cells (NFkB) from peritoneal macrophages against surgical stress.25 Less destruction of intra-abdominal tissues and the favorable effects of a CO2 pneumoperitoneum in Lap-Hx would lead to a lower rate of postoperative ascites. The minimal invasiveness of Lap-Hx improves the postoperative quality of life and reduces surgical morbidities. In this study, we found that the duration of hospital stay in cirrhotic patients with HCC who underwent Lap-Hx was significantly shortened compared with that of the Open-Hx patients. Concerning patient prognoses, several meta-analyses reported that no compromise in prognosis was linked to the
Lap-Hx procedure.9-13 Our study is first to report the long-term (more than 10 years) favorable results of LapHx for HCC in patients with cirrhosis. The 5- and 10-year survival rates of cirrhotic HCC patients who underwent Lap-Hx were 78% and 69%, respectively. In addition, in laparoscopic surgery for colorectal and gastric cancers, no compromise in prognosis was found by a meta-analysis including several randomized control trials.23,26 Despite the comparable oncologic outcomes and some advantages of Lap-Hx for HCC, port-site recurrence has remained a concern.27 We routinely use the surgical porch to retract the resected liver specimen including the HCC from the port site in Lap-Hx, and we have had no patients with port site recurrences or related peritoneal seeding of HCC. The negative impact of surgical morbidity on the recurrence rate and long-term outcomes has been reported in patients with colorectal liver metastasis,28 colorectal cancer,29 gastric cancer,30 and esophageal cancer.31 Reduction of surgical morbidities such as postoperative ascites by the less invasiveness of Lap-Hx for HCC could lead to a survival impact for better prognosis after curative hepatic resection for HCC in patients with cirrhosis in further study. There have been no reported prospective randomized controlled studies of Lap-Hx vs Open-Hx for HCC, and only 1 trial is currently underway in Korea (www. ClinicalTrials.gov Identifier NCT00606385).32 To minimize the selection biases of Lap-Hx, a case-controlled study with propensity score matching for long-term outcomes of Lap-Hx for HCC was reported.33 However, in this study, there were originally no significant differences in the patients’ background characteristics, operation time, intraoperative blood loss, need for transfusion, or tumor-related factors that could affect the patient prognoses between the 2 groups. Based on our encouraging
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short-term and long-term results of Lap-Hx for primary HCC within the Milan criteria irrespective of the HCC location in patients with cirrhosis, well-conducted prospective randomized controlled trials with large numbers of patients are needed to confirm our favorable results. The next challenge of Lap-Hx for HCC should be against huge HCCs and laparoscopic re-resections. The feasibility and safety of Lap-Hx for HCC with a tumor size of 5 to 10 cm34 and laparoscopic re-resection for recurrent HCC35 have been reported, and we are now expanding the indication of Lap-Hx for repeat resections for recurrent HCC.
CONCLUSIONS In conclusion, Lap-Hx for HCC in patients with cirrhosis is associated with less morbidity and shorter hospital stays, with no compromise in patient survival. It may be time to consider changing the standard operation to Lap-Hx for primary HCC within the Milan criteria in patients with cirrhosis. Author Contributions Study conception and design: Yamashita, Ikeda, Kawanaka, Shirabe, Maehara Acquisition of data: Yamashita, Kurihara, Yoshida, Analysis and interpretation of data: Yamashita, Takeishi, Itoh, Harimoto Drafting of manuscript: Yamashita, Ikeda, Shirabe Critical revision: Maehara REFERENCES 1. Hassoun Z, Gores GJ. Treatment of hepatocellular carcinoma. Clin Gastroenterol Hepatol 2003;1:10e18. 2. Yamashita YI, Tsuijita E, Takeishi K, et al. Trends in surgical results of hepatic resection for hepatocellular carcinoma: 1,000 consecutive cases over 20 years in a single institution. Am J Surg 2014;207:890e896. 3. Shimada M, Harimoto N, Maehara S, et al. Minimally invasive hepatectomy: modulation of systemic reactions to operation or laparoscopic approach? Surgery 2002;131:S312e317. 4. Hashizume M, Takenaka K, Yanaga K, et al. Laparoscopic hepatic resection for hepatocellular carcinoma. Surg Endosc 1995;9:1289e1291. 5. Shimada M, Hashizume M, Maehara S, et al. Laparoscopic hepatectomy for hepatocellular carcinoma. Surg Endosc 2001;15:541e544. 6. Ikeda T, Yonemura Y, Ueda N, et al. Pure laparoscopic right hepatectomy in the semi-prone position using the intrahepatic Glissonian approach and a modified hanging maneuver to minimize intraoperative bleeding. Surg Today 2011;41: 1592e1598. 7. Ikeda T, Mano Y, Morita K, et al. Pure laparoscopic hepatectomy in semiprone position for right hepatic major resection. J Hepatobiliary Pancreat Sci 2013;20:145e150.
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