Laparoscopic Versus Open Hepatic Resection for Solitary Hepatocellular Carcinoma Less Than 5 cm in Cirrhotic Patients: A Randomized Controlled Study

Abstract

Background:

Current literature is lacking level 1 evidence for surgical and oncologic outcomes of hepatocellular carcinoma (HCC) undergoing laparoscopic versus open hepatectomy. Aim was to compare feasibility, safety, and surgical and oncologic efficiency of laparoscopic versus open liver resection (OLR) in management of solitary small (<5 cm) peripheral HCC in Child A cirrhotic patients.

Methods:

Patients were randomly assigned to either OLR group (25 patients) or laparoscopic liver resection (LRR) group (LRR: 25 patients). All were treated with curative intent aiming at achieving R0 resection using radiofrequency-assisted technique.

Results:

LLR had significantly less operative time (120.32 ± 21.58 versus 146.80 ± 16.59 minutes, P < .001) and shorter duration of hospital stay (2.40 ± 0.58 versus 4.28 ± 0.79 days, P < .001), with comparable overall complications (25 versus 28%, P = .02). LLR had comparative resection time (66.56 ± 23.80 versus 59.56 ± 14.74 minutes, P = .218), amount of blood loss (250 versus 230 mL, P = .915), transfusion rate (P = 1.00), and R0 resection rate when compared with OLR. After median follow-up of 34.43 (31.67–38.60) months, LLR achieved similar adequate oncological outcome of OLR, no local recurrence, with no significant difference in early recurrence or number of de novo lesions (P = .49). One-year and 3-year disease free survival (DFS) rates, 88% and 59%, in the LLR were comparable to corresponding rates of 84% and 54% in OLR (P = .9).

Conclusion:

LLR is superior to the OLR with significantly shorter duration of hospital stay and does not compromise the oncological outcomes.

Introduction

Laparoscopic liver resection (LLR), unlike many other laparoscopic procedures, has faced difficulties in gaining wide acceptance and popularization since it was first reported in 1992 by Gagner et al.¹ The mandatory requirements of long experience with open liver resection (OLR) combined with a considerable technical laparoscopic expertise led to a significantly long learning curve. This was overshadowed by concerns regarding the efficacy of laparoscopic control of bleeding, adequacy of assessment of the liver for additional lesions in the absence of tactile sensation, and potentially increased risk for gas embolism caused by the pneumoperitoneum through hepatic venous branches during parenchymal transection.² Also, skepticism was raised about the oncological outcomes as measured by the adequacy of surgical resection margin, tumor recurrence rates, and the potential risk for tumor cell seeding through trocar-site or peritoneal dissemination.^3,4

Because most hepatocellular carcinoma (HCC) develops on a background of underlying liver diseases such as chronic hepatitis and liver cirrhosis,⁵ LLR for HCC is still a challenging procedure for both surgeons and patients.^6–9 LLR was indicated for small HCC (<5 cm) located in easily accessible areas (segments II, III, V, VI, and the inferior part of IV).^10,11 The reasons behind the size and site limitation were presumed technical difficulty related to exposure, liver mobilization, control of bleeding, vascular control, absence of manual palpation, fear of massive bleeding, and bile duct injury.^6,9

The number of laparoscopic hepatectomy performed increased exponentially around the world in recent years.¹² The evidence of the advantage of laparoscopic hepatectomy mostly comes from case-matched analysis or case series.^9,13–19 Several studies have reported their comparative results of laparoscopic versus open hepatectomy for HCC.^{2,4,7,14,20–25} Some of these studies have included patients with and without chronic liver disease and others have suffered from low patient numbers and were all case-matched comparative studies. Strong evidence from prospective studies for the superiority of either approach is still lacking and the number of prospective randomized studies conducted to address this particular issue is extremely low. Therefore, the aim of our prospective study is to compare the surgical and oncologic outcomes of the LLR versus OLR in the management of solitary small (<5 cm) peripheral HCC in Child A cirrhotic patients due to hepatitis C infection in a single center.

Patients and Methods

The study was conducted at the Alexandria Main University hospital, Alexandria, Egypt. This is a 1000-bed teaching hospital owned by the Faculty of Medicine of the University of Alexandria. The ethics committee and review board in our institute approved the study and treatment protocol. All HCC patients were discussed at weekly multidisciplinary team conferences consisting of hepatopancreatobiliary (HPB) surgeons, hepatologists, interventional radiologists, and medical and radiation oncologists. An informed consent was obtained from all patients who agreed to participate in the study. The diagnosis of HCC was based on the characteristic dynamic computed tomography (CT) or magnetic resonance imaging (MRI) findings and elevation of the α-fetoprotein (AFP) level (>400 ng/mL). Biopsy was not performed to confirm the diagnosis of HCC.

All patients presenting with solitary HCC <5 cm were assessed for eligibility. Inclusion criteria were in accordance with the international consensus of Louisville for selection of patient for LLR.²⁶ Eligible participants were Child A cirrhotic patients presenting with solitary HCC equal or <5 cm, located in the peripheral segments of the liver II–VI, at a distance from the line of transection, hepatic hilum, and the vena cava, and treatable by limited resection (<3 segments). Exclusion criteria were tumors close to the portal pedicle or hepatic veins, located in segments I, VII, and VIII, an American Society of Anesthesiologists (ASA) score exceeding 3, a decompensated cirrhosis (Child B or C), esophageal varices grade >2, and a platelet count <80 × 10⁹/L, and patients with previous upper abdominal surgeries.

One hundred two patients were assessed; 36 patients were excluded for not meeting the inclusion criteria or if they had an exclusion criterion, whereas 16 patients declined to participate in the study. The remaining 50 patients were randomly assigned to either the OLR group (OLR: 25 patients) or the LRR group (LRR: 25 patients). Randomization was performed using a pseudorandom number generator with individual assignments concealed in sequentially numbered sealed envelopes that were opened in order when assignments were made. An independent observer managed randomization and patients' allocation in either group and the surgeon was informed of the type of surgery to be performed at the time of induction of anesthesia. The same experienced team of hepatobiliary surgeons performed all the OLR and the LRR in both groups. The independent observer also measured the operative time in this study.

The primary endpoint was postoperative duration of hospital stay, while the secondary endpoints included the following: operative time, resection time, amount of blood loss, transfusion requirement, surgical margin status, postoperative complications, 30-day mortality, and recurrence rate.

Sample size estimation

Sample size was calculated using Epi-save software. Postoperative duration of hospital stay of both techniques was used for calculation of sample size of the study. Sample size was estimated to be 21 patients in each group; totally 42 patients were included in the study to detect change of mean hospital stay duration from 4.0 ± 1.8 days among patients subjected to LRR and 8.5 ± 7.0 days among patients subjected to OLR.²⁷ The estimated sample size is made at assumption of 95% confidence level and 80% power of study.

The OLR

OLR was performed by a midline laparotomy or right subcostal incision with an upward midline incision according to tumor location. After laparotomy, exploration was performed for extrahepatic and peritoneal disease. Ultrasonography was performed to confirm tumor location, number, and size in all patients. Extensive liver mobilization was avoided and division of all the suspensory ligaments was performed only if deemed necessary for tumor exposure. Cholecystectomy was not performed except in cases where the transection line was going through the gall bladder bed. The hepatic pedicle was always isolated to enable performance of the Pringle maneuver if needed. After the tumor was localized, the resection line was marked on the liver surface, at least 1 cm away from the edge of the tumor with monopolar diathermy using spray mode. Parenchymal transection was achieved with a scalpel after precoagulation of the transection line using radiofrequency energy (Habib^™ 4X). A second line of ablation parallel to the first line was done to ensure complete tissue coagulation and perfect hemostasis before transection. Bipolar electrocoagulation was used for minor bleeding. If needed, intraparenchymal control of the vessels was obtained with clips or nonabsorbable sutures. In most patients, a 20F drain was placed against the cut surface of the liver.

Laparoscopic liver resection

Patients were maintained in a supine position in the 30° reversed Trendelenburg position, with the surgeon standing between the patient's legs, except for isolated resections of segment VI where the left lateral decubitus position was used to expose the lateral and posterior aspect of the right lobe. The procedures were performed with CO₂ pneumoperitoneum, and abdominal pressure was electronically maintained below 12 mmHg to avoid gas embolism. A 30° laparoscope was used. The mean number of ports used was four (range from 3–5). The operation was usually performed through three 12 mm and one 5 mm ports placed along the subcostal margin depending on the site of liver tumor. In general, two 12 mm ports were inserted to one side and, one 12 and 5 mm ports, respectively, to the other. The liver was explored visually and by intraoperative ultrasonography to confirm the number and size of the lesion and define their relationship with the intrahepatic vascular structures. A tape was placed around the porta hepatis and passed through a 16F rubber drain to be used as a tourniquet to enable a Pringle maneuver to be performed if necessary. Similar to the open approach, the intended transection plane was marked on the surface of liver with diathermy, allowing for at least 1 cm of resection margin, and then a laparoscopic Habib 4X (LH4X) was used to produce coagulative necrosis along the line of intended parenchymal transection. The whole resection line was coagulated as much as possible before transecting the liver parenchyma progressively with a pair of laparoscopic dissection scissors. The most difficult part of the intended plane of transection is that the deepest and farthest areas from the surface of liver receive an additional radiofrequency (RF) application after opening the overlying ablated parenchyma after each RF application in laparoscopic approach. Bipolar electrocoagulation was used for minor bleeding, and larger structures were secured with clips. The resected specimen was placed in a plastic bag by insertion through a 12-mm trocar and retrieved through an enlarged port site or a horizontal, suprapubic Pfannenstiel incision. A 20F drain was routinely placed close to the resection margin. This incision was immediately closed and the abdomen reinflated. The surgical field was irrigated and checked for bleeding or bile leak, and residual fluid was removed by suction. During liver transection in both the open and laparoscopic resections, the central venous pressure was maintained at a low level (<5 mmHg), if possible, by strict control of intravenous fluid administration to reduce venous bleeding from the liver. Fluid replacement was performed once the liver transection was accomplished.

Postoperative management

Patients were transferred to the surgical ward, except when the clinical situation indicated the need for admission to the intensive care unit. Postoperative management protocol was the same for all patients in both groups and included sodium restriction with limited fluid administration, perioperative antibiotics prophylaxis, and proton pump inhibitors. All patients were encouraged to mobilize early and resume feeding as soon as possible. Liver function tests were monitored daily.

Data collection

The following clinical data and treatment outcome in the two groups were recorded and compared: Clinicopathological factors, age, sex, body mass index (BMI), ASA grade, hepatitis serology, esophageal varices, preoperative AFP level, tumor size and location, surgical margin status (a positive resection margin was defined as the presence of tumor cells at the line of transection due to microscopic involvement by the main tumor, venous permeation, or microsatellite nodules), microscopic vascular invasion (defined as the presence of tumor emboli within the central veins or portal or capsular vessels), and histological grade of the primary tumor as defined by Edmondson and Steiner.²⁸ All patients in both groups were treated with curative intent aiming at achieving negative resection margins (R0) after surgical resection. Also, data recorded included operative and postoperative details (operative time, resection time, need for Pringle maneuver, amount of blood loss, blood transfusion requirement, intensive care unit admission, duration of hospital stay, postoperative complications, and 30-day mortality). Specific complications were those related to the liver resection procedure or the underlying liver disease and included the following: bile leak, operative site hemorrhage, ascites hepatic encephalopathy, jaundice, and variceal bleeding. Other complications were recorded as nonspecific complications. Discharge criteria were the ability to tolerate a soft or regular hospital diet, pain control with oral analgesics, and no surgical complication. Postoperative morbidity and mortality were defined as events occurring during the same hospital stay or within 3 months of resection and was graded following the Clavien-Dindo classification.²⁹

Follow-up, survival, and recurrence

After discharge, patients were regularly scheduled for the follow-up outpatient visit and monitored with a standard oncologic protocol, which included liver function tests, AFP, liver imaging with triple-phasic multislice CT and/or MRI at 1 month and then every 3 months during the first 2 years, and then every 6 months thereafter for any intrahepatic recurrence together with annual chest radiography, CT scan, and bone scan for distant metastasis.

Local recurrence was defined as recurrence at surgical resection bed after R0 resection was histopathologically proven. Intrahepatic distant recurrence was defined when new tumor growth that met the previously mentioned criteria for diagnosing HCC appeared remote from the resection bed. Extrahepatic metastasis refers to any recurrence outside the liver. All recurrences were recorded in the database immediately after confirmation of the diagnosis, and the site, number, and size of recurrent tumors were documented. The disease-free survival of patients who recurred was defined as the time from the day of surgery to the day of imaging study that confirmed tumor recurrence. For patients who did not develop recurrent disease, the day of surgery to the day of death or last contact was used.

Statistical analysis of the data

Data were fed to the computer and analyzed using IBM SPSS software package version 20.0. Qualitative data were described using number and percent. Quantitative data were described using mean and standard deviation for normally distributed data, while abnormally distributed data were expressed using median, minimum and maximum. Comparison between different groups regarding categorical variables was tested using Chi-square test. When more than 20% of the cells have expected count <5, correction for chi-square was conducted using Fisher's Exact test or Monte Carlo correction. For normally distributed data, comparison between two groups was done using independent t-test. For abnormally distributed data, comparison between two groups was done using Mann-Whitney test. Kaplan-Meier Survival curve was used. Significance of the obtained results was judged at the 5% level.

Results

Patients in OLR and LLR groups had similar demographic, clinicopathological, preoperative laboratory, and radiological characteristics as shown in Table 1. There was no significant difference between the two groups as regard to age, sex, ASA score, BMI, underlying etiology for liver cirrhosis (hepatitis C infection), Child-Pugh score, tumor size, location, and preoperative laboratory results, including serum bilirubin, liver function tests, and alpha feto protein.

Table 1.

Comparison Between the Two Studied Groups According to Demographic, Clinical, Laboratory, and Tumor Characteristics

	OLR (n = 25)	LLR (n = 25)	P
Age
Minimum–Maximum	41.0–65.0	43.0–66.0	.876
Mean ± SD	54.20 ± 7.41	54.52 ± 7.01	.876
Sex
Male	14 (56.0%)	16 (64.0%)	.773
Female	11 (44.0%)	9 (36.0%)	.773
ASA score
II	21 (84.0%)	20 (80.0%)	1.000
III	4 (16.0%)	5 (20.0%)	1.000
BMI
Minimum–Maximum	25.0–32.0	23.0–36.0	.946
Mean ± SD	27.96 ± 2.03	28.96 ± 1.83	.946
Cause of cirrhosis (HCV)	25 (100.0%)	25 (100.0%)	—
Previous laparotomy	4 (16.0%)	3 (12.0%)	1.000
Child
A5	12 (48.0%)	13 (52.0%)	1.000
A6	13 (52.0%)	12 (48.0%)	1.000
Tumor segments
II	7 (28.0%)	6 (24.0%)	1.000
III	11 (44.0%)	11 (44.0%)
V	2 (8.0%)	3 (12.0%)
VI	5 (20.0%)	5 (20.0%)
Tumor size (cm)
Mean ± SD	3.38 ± 0.59	3.33 ± 0.57		.752
PHT (OV grade II or higher)	10 (40.0%)	12 (48.0%)	.776
Preoperative laboratory result
Serum Bilirubin (mg/dL)	0.90 (0.50–8.0)	0.90 (0.60–0.80)	.722
AST (IU/L)
Minimum–Maximum	58.0–125.0	54.0–130.0	.907
Mean ± SD	82.24 ± 17.52	81.64 ± 18.54	.907
ALT (IU/L)
Minimum–Maximum	67.0–150.0	70.0–142.0	.833
Mean ± SD	100.88 ± 22.91	99.56 ± 21.05	.833
AFP (ng/mL)	226 ± 12.1	230 ± 8.9	.846

Qualitative data were described using number and percent and were compared using Chi-square or Fisher's Exact Test, or Monte Carlo correction. Normally quantitative data were expressed as mean ± SD and compared using student t-test, while abnormally distributed data were expressed using median (min.–max.) and were compared using Mann-Whitney test.

AFI, α-fetoprotein; ALT, alanine transaminase; ASA, American Society of Anesthesiologists physical status classification system; AST, aspartate transaminase; BMI, body mass index; HCV, Hepatitis C virus; LLR, laparoscopic liver resection; OLR, open liver resection; OV, oesophageal varices; PHT, portal hypertension; SD, standard deviation.

All LLRs were successful with no case of conversion to open surgery in the laparoscopic group. There was no significant difference with respect to type or extent of resection; all patients in both groups underwent minor resection (nonanatomical resection) using the radiofrequency-assisted technique. The mean operative time in the OLR group (146.80 ± 16.59 minutes) was significantly longer compared to the LLR group (120.32 ± 21.58 minutes) with P < .001. The mean resection time in the LLR group was 66.56 ± 23.80 minutes (range 24–114 minutes) compared to a mean of 59.56 ± 14.74 minutes (range 35–89 minutes) in the OLR group with no statistically significant difference (P = .218). The amount of blood loss was comparable between two groups with P = 1.00 (median: 230 ml, range: 100–780 in OLR versus 250 ml, range 90–770 ml in LLR). This resulted in no significant difference in the rate of blood transfusion in both groups (P = 1.00), with only one patient who needed transfusion in the OLR group.

Postoperatively, only one patient in the LLR group required 1-day intensive care admission compared to three patients in the OLR group (P = .609). Duration of need for IV narcotic requirement was significantly longer with 2.8 ± 0.3 days in OLR versus 1.0 ± 0.2 days in LLR with P = .0001. Patients in the LLR group had started diet significantly earlier: 0.8 (0.5–1.2) days of postoperative fasting in contrast to 1.5 (1.2–3.2) days of postoperative fasting in the OLR group (P = .001). Time to regular diet was significantly earlier (P < .0001) in the laparoscopic than in the open group (1.1 ± 0.2 days versus 2.8 ± 0.2 days, respectively) The resumption of diet was determined by recovery of bowel sound, patients' tolerance with absence of nausea and vomiting with normalization of bowel gas distribution on simple abdominal X-ray. The patients of LLR group recovered more rapidly, which consequently resulted in significantly shorter hospitalization: 2.40 ± 0.58 days for the LLR group compared to 4.28 ± 0.79 days for the OLR group (P < .001).

Final histopathological reports revealed no significant difference in R0 resection rate between both groups (P = .210), with a mean free resection margin of 1.62 ± 0.45 mm in the OLR group compared to 1.45 ± 0.46 mm in the LLR group, with no case of R1 resection detected on final histopathological examination. Other pathological parameters, including presence of cirrhosis, mean tumor size (P = .752), histological tumor grade (P = .628), and rates of microvascular invasion (P = .769), were not significantly different between the two groups.

Thirty-day mortality rate was 0% in both group and there was no case of 30-day readmissions. The overall postprocedure complications were comparable between both groups (20% in the OLR group versus 12% in the LLR group, P = .702). There was no case of postoperative hemorrhage or bile leak in both groups. In the OLR group, five patients had a total of 15 complications, ascites requiring treatment (n = 4), temporary hyperbilirubinemia (n = 2), mild pleural effusion (n = 2), wound infection (n = 2), chest infection (n = 2), wound hematoma (n = 1), and incisional hernia (n = 2). In the LLR group, three patients had five complications, including ascites requiring treatment (n = 2), chest infection (n = 1), pleural effusion (n = 1), and wound infection (n = 1). None of our patients in both groups suffered from postoperative liver failure, variceal bleeding, encephalopathy, or intra-abdominal abscess. There was no significant difference in the incidence, type, and severity of complications as classified using Clavien-Dindo grade (P = .634) as shown in Table 2.

Table 2.

Comparison Between the Two Studied Groups According to Perioperative Data, Tumor Characteristics, and Postoperative Morbidity

	OLR (n = 25)	LLR (n = 25)	P
Type of resection (Nonanatomical)	25 (100.0%)	25 (100.0%)	—
Operative time (minutes) Mean ± SD Range	146.80 ± 16.59 (110–180)	120.32 ± 21.58 (88–170)	<.001^*
Blood loss in mL (median, range)	230.0 (100.0–780.0)	250.0 (90.0–770.0)	.915
Resection time (minutes) Mean ± SD Range	59.56 ± 14.74 (35–89)	66.56 ± 23.80 (24–114)	.218
Intraoperative transfusion	1 (4.0%)	0 (0.0%)	1.000
Portal clamping	1 (4.0%)	0 (0.0%)	1.000
Conversion	—	0 (0.0%)	—
Margins R0 (Free)	25 (100.0%)	25 (100.0%)	—
Associated procedures (cholecystectomy)	2 (8.0%)	1 (4.0%)	1.000
IV narcotic requirement (days)	2.8 ± 0.3	1.0 ± 0.2	.0001^*
Time to regular diet (days)	2.8 ± 0.2	1.1 ± 0.2	.0001^*
Mortality	0 (0.0%)	0 (0.0%)	—
ICU stay (days)
No	22 (88.0%)	24 (96.0%)	.609
Yes	3 (12%)	1 (4.0%)
Hospital stay (days)	4.28 ± 0.79	2.40 ± 0.58	<.001^*
Postoperative complications (patient)	5 (20%)	3 (12%)	.702
Specific:
Bleeding	0 (0.0%)	0 (0.0%)	—
Ascites	4 (16.0%)	2 (8%)	.667
Liver failure	0 (0.0%)	0 (0.0%)	—
Jaundice	2 (8.0%)	0 (0.0%)	.490
Encephalopathy	0 (0.0%)	0 (0.0%)	—
Bile leak	0 (0.0%)	0 (0.0%)	—
Non specific
Chest	2 (8.0%)	1 (4.0%)	1.000
Pleural effusion	2 (8.0%)	1 (4.0%)	1.000
Incisional hernia	2 (8.0%)	0 (0.0%)	.490
Hematoma	1 (4.0%)	0 (0.0%)	1.000
Wound	2 (8.0%)	1 (4.0%)	1.000
Clavian-Dindo classification
Nonsevere (grade 1–2)	4 (16.0%)	3 (12.0%)	.508
Severe (grade 3–4)	1 (4.0%)	0 (0.0%)	1.000

Statistically significant at P ≤ .05.

OLR, open liver resection; LLR, laparoscopic liver resection; SD, standard deviation; ICU, intensive care unit.

After a median follow-up of 34.43 months (range, 18–39.20 months), none of the surgical resected tumors in both groups showed local recurrence. There was no significant difference between the two groups in incidence or type of recurrence, whether isolated intrahepatic (P = .655) or combined intrahepatic and extrahepatic recurrence (P = 1.000). Nine patients (36%) in OLR group developed intrahepatic distant recurrence compared to 7 (28%) patients in the LLR group (P = .655), as illustrated in Table 3, with no significant difference in the mean number of new (de novo) tumors detected in the OLR (2.4 ± 1.40) or LLR group (2.41 ± 1.49; P = .45). Recurrences related to laparoscopy, such as peritoneal dissemination and port-site recurrences, were not observed in the LLR group. In the LLR group, retreatment for recurrent tumors was done in 6/7 patients with isolated intrahepatic recurrence, including repeat resection in two patients, radiofrequency ablation (RFA) in three patients, and chemoembolization in one patient, whereas one patient (1/7) could not be treated further because of poor liver function. In the OLR group, recurrent intrahepatic tumors were treated by RFA (n = 5) or chemoembolization (n = 3), and one patient had radio embolization. Patients in both groups who developed combined intrahepatic and extrahepatic recurrence received targeted therapy. Kaplan-Meier survival curves in Figure 1 shows that the LLR group achieved similar disease-free survival to the OLR group (P = .849). The 1- and 3-year disease-free survival was 88% and 58.7%, and 84% and 54% for the LLR and OLR groups, respectively.

FIG. 1.

Kaplan-Meier survival curve for disease-free survival.

Table 3.

Comparison Between the Two Studied Groups According to Histopathology Data and Recurrence Rate and Pattern

	OLR (n = 25)	LLR (n = 25)	P
Histological grade
Poor differentiated	4 (16.0%)	3 (12.0%)	.628
Moderate differentiated	12 (48.0%)	9 (36.0%)
Well differentiated	9 (36.0%)	13 (52.0%)
Microvascular invasion	17 (68.0%)	15 (60.0%)	.769
Resection margin (cm)	1.62 ± 0.45	1.45 ± 0.46	.210
30-Day readmission	0 (0.0%)	0 (0.0%)	—
Recurrence	11 (44.0%)	10 (40.0%)	.774
Port-site recurrence	NA	0 (0.0%)	—
Intrahepatic recurrence	9 (36.0%)	7 (28.0%)	.655
Combined intrahepatic and extrahepatic recurrence	2 (8.0%)	3 (12.0%)	1.000

OLR, open liver resection; LLR, laparoscopic liver resection; SD, standard deviation.

Discussion

LLR poses a true technical challenge for surgeons due to the peculiar and variable vascular and biliary anatomical features of the liver. The presence of cirrhosis in HCC patients undergoing LLR makes parenchymal transection an even more delicate and demanding procedure,²³ with increased concerns about the occurrence of massive hemorrhage and bile leak during parenchymal transections.^23,25 Published literature has shown evidence on the benefits of laparoscopic approach as a minimally invasive procedure in patients having liver resection with no compromise to the margin status or overall survival.^{13,14,16,25,27,30–32} Few studies have compared the results of LLR versus OLR for HCC patients in presence of cirrhosis, the majority of these were case series and included both cirrhotic and noncirrhotic patients.^{7,8,14,20,22–25,32–35} LLR has not gained much popularity among surgeons due to concerns and controversies related to resection margins, tumor seeding, incision-related metastasis, and the risk of inadequate tumor resection.²⁴

According to our results, in Child A cirrhotic patients with solitary HCC <5 cm, LLR has provided a significantly shorter operative time with faster recovery and a significant reduction in duration of postoperative hospital stay, while maintaining comparable amount of blood loss, transfusion rate, resection time, and overall morbidity and mortality to OLR. Moreover, LLR did not compromise the oncological outcomes with similar rates of R0 resection, recurrence, and disease-free survival to OLR.

The significant reduction in duration of hospital stay (2.40 ± 0.58 days in LLR versus 4.28 ± 0.79 days in OLR, P < .001) was a reflection of significantly faster postoperative recovery in the LLR group compared to the OLR group where patients started diet significantly earlier (P = .001), the time to regular diet was shorter (1.1 ± 0.2 days in LLR versus 2.8 ± 0.2 days OLR, P < .0001), and the duration of need for IV narcotic was significantly shorter (1.0 ± 0.2 days in LLR versus 2.8 ± 0.3 days in OLR, P = .0001). By decreasing surgical stress, laparoscopic surgery results in reduced postoperative pain and need for analgesic drugs, earlier ambulation and oral food intake, faster recovery, and faster hospital discharge. These findings are consistent with laparoscopic procedures where patients have faster ambulation, early oral intake, and reduced analgesic requirements. Other studies have reported that the LLR has a significant advantage for shortening hospital stay and reduced complication,^17,36,37 included both cirrhotic and noncirrhotic patients with different tumor pathology; however, our prospective study inclusion of only HCC <5 cm provides a strong level of evidence on the same conclusion among cirrhotic patients.

Laparoscopic approach was completed successfully in all patients in the LLR group, with no need to conversion to open surgery (conversion rate 0%). This was attributed to both increased experience with laparoscopic resection and inclusion of only peripheral easily-resectable solitary HCC away from hepatic pedicle, major hepatic veins and vena cava. The operative time for the OLR group (146.80 ± 16.59 minutes) was significantly longer (P < .001) than the LLR group (120.32 ± 21.58 minutes), despite having similar resection time (59.56 ± 14.74 versus 66.56 ± 23.80, P = .218), reflecting the need of longer time in performing and closing the incision.

Some authors have reported reduced total amount of blood loss in LLR compared to open surgery, and they attributed it to image magnification and intraoperative pneumoperitoneum.^7,8 However, in our study, we had a similar amount of blood loss and transfusion rates in both LLR and OLR groups. This may be explained by the following: first; the use of the same parenchymal transecting energy device in both LLR and OLR, in contrast to these studies where the parenchymal transecting technique and devices used were not unified. Second: the good view with magnification enabling meticulous hemostasis was achieved through the use of surgical loops in open surgery and the high-definition laparoscopy in the LLR group. Third: the added value of high pneumoperitoneum pressure in reducing bleeding from hepatic veins was not evident in our results due to selection of peripheral hepatocellular carcinomas (HCCS) located at a distance from major vascular structures.

In our study, no case of 30-day mortality or 30-day readmissions was encountered in both groups and the overall postprocedure complications (20% in the OLR group versus 12% in the LLR group) were comparable between both groups (P = .702). There was no significant difference in the incidence, type, and severity of complications, as classified using Clavien-Dindo grade. LRR was reported to be associated with reduced postoperative morbidity, particularly the incidence of developing postoperative ascites and liver failure. The assumed explanation was the preservation of abdominal wall musculature with its parietal collateral circulation due to the absence of long abdominal incisions and preservation of the round ligament, which may contain significant collateral veins.^7,38–42 In our study, 16% of patients in the OLR group had postoperative ascites compared to 8% in patients with LLR; however, it did not reach a statistically significant value (P = .667).

In view of our results, both LLR and OLR achieved technical oncological success with similar R0 resection rates. The R0 resection with adequate tumor-free margin is a well-established prognostic indicator of HCC,⁴³ and a positive histologic margin was associated with a higher incidence of postoperative HCC recurrence.⁴⁴ Tumor recurrence after hepatic resection is the main cause of late death of patients with HCC. Most series in the literature^{13,17,19,23,33,45,46} revealed no difference in resection margin between LLR and OLR, with two studies showing a wider margin in the LLR group.^21,47 Considering their study design, patients with tumor close to major vascular structures were selected for the open surgical approach. Due to absence of tactile sensation in LRR, intraoperative ultrasonography is mandatory tool with high sensitivity for accurate identification of number, site, size, and extent of hepatic tumors, with planning and marking the planned lines of resection.^48,49 All our patients in both groups were cirrhotic secondary to hepatitis C infection, and even with the presence of tactile feedback in the OLR group, surgeons did not find it of any help to delineate and mark the resection margins due to hard texture of the liver in the presence of cirrhotic nodules and have depended mainly on intraoperative ultrasound to accurately mark the resection margins in the cirrhotic parenchyma. Another major concern about LRR of HCC was the risk of tumor peritoneal dissemination and port-site metastases. The use of a plastic bag for specimen retrieval was of help to prevent this complication. Neither peritoneal carcinomatosis nor port-site recurrence was observed following HCC resection by laparoscopy in the LLR group, highlighting the conclusion that LRR does not increase the risk of tumor recurrence or compromise oncological outcomes.

The main advantage of this study is its prospective design with consecutive enrollment of patients with solitary HCC <5 cm in Child A cirrhotic patients. The inclusion criteria allowed the pure expression of surgical and oncological outcomes of LLR versus the OLR approach by eliminating the effect of other confounding factors of either poor liver condition (Child B and C) or tumor size, location, and stage to eliminate bias and improve the validity of our results.

In conclusion, in Child A cirrhotic patients with solitary HCC <5 cm, LLR is superior to OLR in providing faster recovery, shorter operative time, and reduced duration of postoperative hospital stay, without compromising the oncological outcomes, achieving similar disease-free survival compared with OLR.

Footnotes

Disclosure Statement

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. No competing financial interests exist.

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