Meta-Analysis of Trials Comparing Minimally-Invasive and Open Liver Resections for Hepatocellular Carcinoma

Journal of Surgical Research 171, e33–e45 (2011) doi:10.1016/j.jss.2011.07.008

Meta-Analysis of Trials Comparing Minimally-Invasive and Open Liver Resections for Hepatocellular Carcinoma Alessandro Fancellu, M.D.,*,1 Alan S. Rosman, M.D., F.A.C.P.,† Valeria Sanna, M.D.,‡ Giuseppe R. Nigri, M.D.,§ Luigi Zorcolo, M.D.,k Michele Pisano, M.D.,{ and Marcovalerio Melis, M.D.# *Department of Surgery-Institute of Clinica Chirurgica, University of Sassari, SS, Italy; †Section of Gastroenterology and Medicine Program, Mount Sinai School of Medicine and Bronx VAMC, New York, New York; ‡Department of Oncology, ASL n.1 Sassari, SS, Italy; §Department of Surgery, St. Andrea Hospital, Sapienza University of Rome, RM, Italy; kDepartment of Surgery, University of Cagliari, CA, Italy; {Department of Surgery, Ospedali Riuniti di Bergamo, BG, Italy; and #Division of Surgical Oncology, New York University School of Medicine, NY Harbor Healthcare System VAMC, New York, New York Originally submitted March 27, 2011; accepted for publication July 7, 2011

Background. Recent literature suggests that minimally-invasive hepatectomy (MIH) for hepatocellular carcinoma (HCC) is associated with better perioperative results and similar oncologic outcomes compared to open hepatectomy (OH). However, previous reports have been limited by small sample size and single-institution design. Methods. To overcome these limitations, we performed a meta-analysis of studies comparing MIH and OH in patients with HCC using a random-effects model. Results. Nine eligible studies were identified that included 227 patients undergoing MIH and 363 undergoing OH. Patients were similar respect to age, gender, rates of cirrhosis, hepatitis C infection, tumour size, and American Society of Anesthesiology classification. The MIH group had lower rates of hepatitis B infection. There were no differences in type of resection (anatomic or non-anatomic), use of Pringle’s maneuver, and operative time. Patients undergoing MIH had less blood loss [difference L217 mL; 95% confidence interval (CI), –314 to L121], lower rates of transfusion [odds ratio (OR), 0.38; 95% CI, 0.24 to 0.59], shorter postoperative stay (difference L5 days; 95% CI, –7.84 to L2.25), lower rates of positive margins (OR, 0.30; 95% CI, 0.12 to 0.69) and perioperative complications (OR, 0.45; 95% CI, 0.31 to 0.66). Survival outcomes were similar in the two groups. Conclusions. Although patient selection might have influenced some of the observed outcomes, MIH was 1 To whom correspondence and reprint requests should be addressed at Department of Surgery-Institute of Clinica Chirurgica, University of Sassari, V.le San Pietro, 43, 07100 Sassari, Italy. E-mail: [email protected].

associated with decreased blood loss, transfusions, rates of positive resection margins, overall and specific morbidity, and hospital stay. Survival outcomes did not differ between MIH and OH, although further studies are needed to evaluate the impact of MIH on longterm results. Ó 2011 Elsevier Inc. All rights reserved. Key Words: hepatocellular carcinoma; minimally invasive; laparoscopy; open hepatectomy.

INTRODUCTION

Hepatocellular carcinoma (HCC) is the most common primary liver cancer and one of the most common malignancies in the world, accounting for approximately one million deaths per year [1]. Curative options for HCC include resection and liver transplantation. Percutaneous ablative techniques are accepted as an attractive alternative to surgery in patients with small-size HCC; however, large studies suggest that resection is associated with lower tumor recurrence and better survival [2–5]. Open hepatectomy (OH) has traditionally been the primary treatment for resectable HCC in patients with preserved liver function or well compensated cirrhosis who are not transplant candidates [5–7]. In recent years, advances in minimally-invasive liver resection techniques have led to a surge in minimallyinvasive hepatectomy (MIH) for HCC [8–10]. Benefits of laparoscopic liver resection may include reduced postoperative pain, decreased length of recovery, and lower complication rates [8–12]. However, most of the studies reporting on MIH are retrospective,

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single-institution case series of a relatively small number of patients and included both metastatic and primary liver neoplasms, thus resulting in limited statistical power for evaluation of outcomes after laparoscopic resection of HCC. In 2007 Simillis et al. performed a meta-analysis of studies comparing MIH and OH for benign and malignant neoplasms, however survival items and outcomes specifically related to HCC treatment were not addressed [10]. In 2009, an updated meta-analysis of studies comparing laparoscopic versus open resection for benign and malignant tumors was published and reported on 1906 hepatic resections from twenty-six studies [13]. The authors concluded that long-term survival for malignant tumors (thus including HCC, metastases, and other primaries) is comparable in the two groups and that the use of laparoscopic hepatic resection for benign and malignant tumors is a safe alternative to open hepatic resection. However, a comparison between MIH and OH specifically for HCC was not addressed and important issues of surgical treatment of HCC, such as coexistence of cirrhosis, tumor size, and extension of hepatic resection were unexamined. Moreover, since that time new articles comparing MIH and OH for HCC have been added to the literature. We performed a metaanalysis of studies comparing MIH and OH specifically for HCC. MATERIALS AND METHODS

below) were not reported or impossible to calculate for both minimally invasive and open techniques.

Data Extraction Two reviewers independently identified the potentially relevant articles and extracted the following data: first author, year of publication, study population characteristics, study design, number of subjects operated on with each technique, conversion rate from minimally invasive to open technique, tumor characteristics, operation related factors, perioperative outcomes, disease-free and overall survival. In few instances data not originally reported in the study was obtained directly from the authors.

Outcomes of Interest and Definitions For the purposes of this study, we defined anatomic resections those hepatectomies guided by the intra-hepatic anatomy as described by Couinaud (e.g., removal of one or more segments) [14], and nonanatomic resection those minor hepatectomies involving less than one segment (e.g., wedge resections). All the studies were abstracted for the following relevant data: - Patients baseline characteristics: age, gender, rates of hepatitis B and C infection, ASA (American Society of Anesthesiology) score, rates of cirrhosis, and tumor size. - Operation-related outcomes: extent of resection (number of segments removed, anatomic resections versus non-anatomic resection), conversion rate, operative time, need and duration for Pringle maneuver, blood loss, rates of transfusion, status of resection margins (positive versus negative), width of resection margins. - Duration of postoperative hospital stay. - Postoperative complications: mortality, overall and specific morbidity. - Duration of follow-up and long-term outcomes including diseasefree and overall survival.

Study Selection A systematic literature search was performed using Embase, Medline, Cochrane, and PubMed databases, for studies comparing MIH to conventional OH, by using the following keywords: ‘‘minimallyinvasive’’ or ‘‘laparoscopic’’ or ‘‘laparoscopy’’ and ‘‘hepatocellular carcinoma’’ or ‘‘hepatic resection.’’ The ‘‘related articles’’ function was used to broaden the search and all abstracts, studies, and citations scanned were reviewed as well as the references of relevant articles. The latest date for this search was October 31, 2010. No language restrictions were made.

Inclusion Criteria To be included in this meta-analysis, studies had to: (1) compare MIH (pure laparoscopic or hand-assisted laparoscopy) and OH in patients undergoing resection for HCC; (2) include at least 10 patients in each group; (3) report on at least one of the outcomes of interest mentioned below; (4) contain a previously unreported patient group. If patient material was reported more than once by the same institution, the most informative and/or recent article was included in our analysis.

Exclusion Criteria We excluded from our meta-analysis: (1) trials comparing minimally-invasive and open resection for ‘‘hepatic neoplasms’’ in which it was impossible to extract the data specifically related to HCC patients; (2) studies in which the outcomes of interest (specified

Statistical Analysis Meta-analysis was performed in line with recommendations from the Preferred Reporting Items for Systematic Reviews and MetaAnalyses (PRISMA) statement [15]. Variables were pooled only if evaluated by three or more studies. Both qualitative and quantitative data were pooled using a random-effects model. The rates of conversion from a laparoscopic to an open procedure were pooled using the inverse of the variance of the rates [16, 17]. The 95% confidence intervals for rates were calculated using standard statistical methods [18]. In dealing with rates equal to zero, an alternate method described by Hanley and Lippman-Hand [19] was used. For data derived from contingency tables (e.g., complication rates for laparoscopic and open procedures), we computed the odds ratio (OR) and 95% confidence interval (CI) [20]. In cases of unstable estimators (which occur if the rate of an event is either 0 or 1), 0.5 was added to all the cells to estimate the odds ratio [18, 21]. An odds ratio significantly less than 1 favored laparoscopic surgery, whereas an odds ratio significantly greater than 1 favored the open procedure. For continuous variables (e.g., length of operation, days of hospital stay), we calculated the difference in mean values between the two procedures and its 95% confidence interval [20]. This method requires that the study report the standard errors of the mean, the standard deviations, or the confidence intervals. Thus, studies that did not report any of these parameters were not included in the statistical pooling of continuous variables. The outcome variables (e.g., rates, odds ratios, and difference in mean values) were pooled using a random-effects model according to the method of Der Simonian and Laird [22], as further described by Fleiss [21]. We tested for homogeneity using the

FANCELLU ET AL.: META-ANALYSIS OF LIVER RESECTIONS FOR HCC random-effects model to calculate the Q statistic and associated p value [20]. The outcome values (either odds ratios or difference in means) and their 95% confidence intervals are reported. All P values <0.05 (two-tailed) were considered significant. Funnel plots were constructed as described by Peters et al. [23] in order to assess for publication bias. For qualitative outcomes, precision (as defined by the inverse of the standard error of the odds ratio) was plotted against the odds ratio on a logarithmic scale. For quantitative variables, the pooled difference in outcomes between laparoscopic and open surgery was used for the x-axis. A broken vertical line was also plotted to indicate the pooled odds ratio or difference in outcome. The lack of studies with negative outcomes and low precision would produce an asymmetric plot and suggest a publication bias.

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RESULTS Included Studies

The PRISMA flow diagram for systematic review is presented in Figure 1. Nine studies comparing MIH and OH for patients with a solitary HCC, published between January 2001 and October 2010, were considered suitable for the meta-analysis [6, 25–32]. On review of the data extraction, there was 100% agreement between the two reviewers. Three

FIG. 1. Selection of articles for meta-analysis [12, 24].

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TABLE 1 Characteristics of Studies Included in the Meta-analysis Author/year of publication

Study design

No. of patients undergoing MIH

No. of patients undergoing OH

Selection criteria for MIH

Prospective (MIH) matched retrospective (OH)

16

16

HCC < 12 cm in diameter, located in the Couinaud segments 2 to 6

Tranchart et al. [32], 2010

Prospective (MIH) matched retrospective (OH)

42

42

Endo et al. [31], 2009

Retrospective

10

11

Compensated cirrhosis or noncirrhotic liver, esophageal varices grade  1, PLT count  80 x 109/l, tumors well clear from the portal pedicle or hepatic veins, ASA score  3 HCC < 5 cm in diameter, located in The Couinaud segments 2 or 3

Belli et al. [29], 2009

Retrospective

54

125

Sarpel et al. [28], 2009

Retrospective matched

20

56

Lai et al. [27], 2009

Prospective (MIH) matched retrospective (OH)

25

33

Normal livers or Child class A cirrhosis, HCC < 5 cm in diameter, located in the Couinaud segments 2 to 6

Kaneko et al. [25], 2005

Prospective (MIH) matched retrospective (OH)

30

28

HCC < 6 cm in diameter, solid, located in the Couinaud segments 2 to 6

Well compensated cirrhosis (Child-Pugh class A/B low grade) without signs of severe portal hypertension, PLT count 80 x 109/l, exophytic or subcapsular tumor < 5 cm in diameter located in the Couinaud segments 2 to 6 n/r

MIH feasible and safe in selected patients with HCC, with good surgical results and similar outcomes in terms of OS and DFS Better postoperative outcome without oncologic consequences in selected patients undergoing MIH

MIH in LLH superior to OH in terms of short-terms results without deterioration of long-term survival. MIH alternative choice for treatment of HCC MIH in cirrhotic liver feasible and safe in selected patients with adequate long-term survival and recurrence when stratified for tumor characteristics related to survival outcome

MIH and OH no significantly different in terms of margin status, recurrence, or survival; MIH reasonable alternative to OH in selected cases MIH for HCC feasible and safe in selected patients; midterms survival favorable; shorter hospital stay; importance of expert surgical team MIH beneficial for patient quality of life without some disadvantages of OH in selected patients

JOURNAL OF SURGICAL RESEARCH: VOL. 171, NO. 1, NOVEMBER 2011

Aldrighetti et al. [30], 2010

Main authors’ conclusions

Laurent et al. [6], 2003

Prospective (MIH) matched retrospective (OH)

13

14

Subcapsular HCC < 5 cm in diameter, located in the Couinaud segments 2 to 6

Shimada et al. [26], 2001

Retrospective matched

17

38

Small, well demarcated and peripheral HCC located in the Couinaud segments 2 to 6

Rate of decompensation of liver disease lower after MIH for subcapsular HCC complicating chronic liver disease Better short-term outcome for MIH; long-term prognosis similar; MIH alternative for treatment of selected cirrhotic patients

TABLE 2 Comparisons of Baseline Characteristics No. of patients

Mean age (y)

Proportion male no. (%)

Hepatitis B carrier no. (%)

Hepatitis C carrier no. (%)

Proportion with chronic liver disease/cirrhosis no. (%)

Mean size of tumor (cm)

ASA score (mean)

Author

MIH

OH

MIH

OH

MIH

OH

MIH

OH

MIH

OH

MIH

OH

MIH

OH

MIH

OH

Aldrighetti Endo Tranchart Belli Sarpel Lai Kaneko Laurent Shimada

16 10 42 54 20 25 30 13 17

16 11 42 125 56 33 28 14 38

65 72 63 63 63 59 59 62 62

71 64 65 61 58 59 61 65 63

11 (68.7) 8 (80.0) 27 (64.3) 31 (57.0) 15 (75.0) 18 (72.0) 18 (60.0) 10 (77.0) 15 (88.0)

12 (75.0) 8 (72.7) 28 (66.7) 78 (62.0) 45 (80.0) 21 (64.0) 18 (64.0) 10 (71.0) 24 (63.0)

n/r 2 (20.0) n/r 2 (3.7) n/r 23 (92.0) 4 (13.3) 4 (3.8) 2 (11.8)

n/r 3 (27.3) n/r 16 (12.8) n/r n/r n/r 6 (42.8) 7 (18.4)

n/r 8 (80.0) n/r 50 (92.6) n/r 1 (4.0) 21 (70.0) 5 (38.5) 12 (70.6)

n/r 5 (45.4) n/r 102 (81.6) n/r n/r n/r 5 (35.7) 24 (63.1)

9 (56.2) 6 (60.0) 31 (73.8) 54 (100) 9 (45.0) 23 (92.0) 13 (43.3) 13 (100) 13 (76.5)

9 (56.2) 9 (81.8) 34 (80.9) 125 (100) 27 (48.2) 31 (93.9) n/r 14 (100) 28 (73.7)

4.00 3.00 3.58 3.80 4.30 n/r 3.00 3.35 2.60

4.6 4.1 3.68 6.00 4.30 n/r 3.10 3.43 2.50

2.12 n/r 2.09 1.87 n/r n/r n/r n/r n/r

2.50 n/r 2.11 1.84 n/r n/r n/r n/r n/r

FANCELLU ET AL.: META-ANALYSIS OF LIVER RESECTIONS FOR HCC

MIH ¼ minimally invasive hepatectomy; OH ¼ open hepatectomy; HCC ¼ hepatocellular carcinoma; OS ¼ overall survival; DFS ¼ disease-free survival; PLT ¼ platelet; ASA ¼ American Society of Anesthesiology; LLH ¼ left lateral hepatectomy.

MIH ¼ minimally invasive hepatectomy; OH ¼ open hepatectomy; ASA ¼ American Society of Anesthesiology.

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studies were conducted in Japan, one in the USA, two in Italy, one in Hong Kong, and two in France. The reports were primarily retrospective studies of comparable patients. No randomized trials were identified. A total of 227 patients underwent MIH and 363 had OH. The characteristics of the studies are summarized in Table 1.

two cases the lesions were located in the segments 7 and 8 [25, 30]. In two studies MIH was considered only for subcapsular tumor location [6, 29]. One study was restricted to left lateral lobectomies (segments 2 and 3) [31]. Perioperative Outcomes (Table 3)

Operative Parameters

Patient Characteristics

Baseline characteristics of the studies are summarized in Table 2. Patients in the two groups were similar with respect to age (63 versus 62 years; difference, 0.44; 95% CI, –2.88 to 3.78), rates of male gender (0.67 versus 0.67; OR, 0.93; 95% CI, 0.65 to 1.34), cirrhosis (0.80 versus 0.82; OR, 0.75; 95% CI, 0.45 to 1.22), rates of hepatitis C infection (0.79 versus 0.72; OR, 1.87; 95% CI, 0.86 to 4.05), ASA classification (average ASA score 1.99 versus 1,97; difference, –0.03; 95% CI, –0.36 to 0.30) and tumor size as measured by the pathologist (3.53 versus 4.53 cm; difference, –0.51 cm; 95% CI, –1.20 to 0.18). The MIH group had lower rates of hepatitis B infection than the OH group (0.10 versus 0.17; OR 0.40; 95% CI, 0.21 to 0.76). The manuscripts considered did not report specifically on degree of cirrhosis (i.e., Child class) and this data was not included in our analysis. Eight studies indicated tumor characteristics required for laparoscopic approach [6, 25–27, 29–31]. They included solitary HCC of maximum size of 5 [6, 26, 27, 29, 31], 6 cm [25] or 12 cm [30], mostly located in the left (segments 2–4) or right anterior lateral segments (5 and 6). Only in

Eight studies specified the type of resection performed. Only three authors reported on laparoscopic resections including more than two segments [27, 29, 32]. There were no differences between MIH and OH groups in type of resection performed (i.e., anatomic versus non-anatomic) (rates of non-anatomic resection 0.38 versus 0.39; OR, 0.92; 95% CI, 0.55 to 1.55), use Pringle’s maneuver (rates 0.10 in the MIH group and 0.23 in the OH group; OR, 0.15; 95% CI, 0.01 to 2.08), operative time (195 versus 193 min; difference, –2,22; 95% CI, –25.60 to 21.16) (Fig. 2A). The width of the resection margins was not significantly different (10.57 versus 9.37 mm; difference, 0.54; 95% CI, –0.70 to 1.80). The rates of positive margins were lower for the MIH group (0.09 versus 0.18; OR 0.30; 95% CI, 0.12 to 0.69) (Fig. 2B). Patients undergoing MIH had significantly less blood loss (361 mL versus 603 mL; difference, –217 mL; 95% CI, –314 to 121) (Fig. 2C) and required fewer transfusions (transfusion rates 0.10 versus 0.21; OR 0.38; 95% CI, 0.24 to 0.59) (Fig. 2D). The rates for conversion to an open procedure ranged from 0 to 0.15. The pooled rate was 0.04 (95% CI, 0.02 to 0.07).

TABLE 3 Comparisons of Perioperative Outcomes Variables Operative Non-anatomic resections Anatomic resections > 1 seg Anatomic resection ¼ 1 seg Pringle maneuver Operative time (min) Evaluated blood loss (ml) Patient transfused (%) Resection margin width (mm) Positive resection margins Postoperative Mean hospital stay (days) Overall morbidity Liver failure Ascites Bile leak Postoperative hemorrhage Pulmonary complications Mortality

No. of pooled studies

Mean MIH

Mean OH

Difference or odds ratio

95% LL CI

95% UL CI

6 5 6 4 7 6 6 5 5

0.38 0.37 0.23 0.10 195 361 0.10 10.57 0.09

0.39 0.28 0.27 0.23 193 603 0.21 9.37 0.18

0.92 1.32 0.73 0.15 2.22 217 0.38 0.54 0.30

0.55 0.61 0.42 0.01 25.60 314 0.24 0.70 0.12

1.55 2.86 1.28 2.08 21.16 121 0.59 1.80 0.69

7 9 4 3 4 3 5 7

10.36 0.15 0.04 0.05 0.02 0.08 0.03 0.01

13.62 0.25 0.15 0.23 0.05 0.05 0.07 0.03

5.04 0.45 0.22 0.20 0.43 1.31 0.34 0.44

7.84 0.31 0.11 0.10 0.13 0.32 0.13 0.17

2.25 0.66 0.44 0.40 1.38 5.36 0.87 1.11

MIH ¼ minimally-invasive hepatectomy; OH ¼ open hepatectomy; seg ¼ segment; min ¼ minutes; mL ¼ milliliters; mm ¼ millimeters.

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FIG. 2. Operative outcomes. (A) Meta-analysis of operative time. (B) Meta-analysis of positive margins. (C) Meta-analysis of intraoperative blood loss. (D) Meta-analysis of transfusion rates.

Postoperative Course

Assessment for Publication Bias

Patients in the MIH group had a shorter postoperative stay (10.36 versus 13.62 days; difference, –5.04, 95% CI, –7.84 to 2.25) (Fig. 3A) and fewer overall complications (0.15 versus 0.25; OR, 0.45; 95% CI, 0.31 to 0.66) (Fig. 3B). Analysis of specific morbidity revealed that rates of liver failure were decreased in MIH group (0.04 versus 0.15; OR, 0.22; 95% CI, 0.11 to 0.44) (Fig. 3C), as well as postoperative ascites (0.05 versus 0.23; OR, 0.20; 95% CI, 0.10 to 0.40) and pulmonary complications (0.03 versus 0.07; OR, 0.34; 95% CI, 0.13 to 0.87). There were no significant differences between MIH and OH groups in postoperative hemorrhage (0.08 versus 0.05; OR, 1.31; 95% CI, 0.32 to 5.36) and bile leak (0.02 versus 0.05; OR, 0.43; 95% CI, 0.13 to 1.38). Thirty-day mortality was lower for MIH group but the difference just fell short of statistical significance (OR, 0.44; 95% CI, 0.17 to 1.11) (Fig. 3D).

Funnel plots (shown in Figs. 4 and 5) were constructed in order to assess for publication bias. The plots for the outcomes operative time, positive margins, intraoperative blood loss, transfusion rates, hospital days, and postoperative liver failure (Fig. 4A–D, Fig. 5A and C) demonstrated some symmetry. In contrast, the plots for overall morbidity and 30-day mortality (Fig. 5B and D) suggested a decreased number of positive studies with low precision. This is generally not seen with typical publication bias. Survival (Table 4) All studies compared oncologic results of MIH and OH. Three-year overall survival rates were 0.72 and 0.64, respectively, for MIH and OH. Five-year overall survival rate were 0.63 and 0.56, respectively, for MIH and OH.

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FIG. 3. Postoperative outcomes. (A) Meta-analysis of hospital stay. (B) Meta-analysis of postoperative overall morbidity. (C) Meta-analysis of postoperative liver failure. (D) Meta-analysis of 30-d mortality.

On the whole, no differences were found between MIH and OH in overall- and disease-free survival.

DISCUSSION

Development of laparoscopic approach for liver malignancies has been slow compared with the development of this procedure in other fields of surgical oncology. Wide acceptance of this technique has been delayed by concerns regarding technical difficulties, risk of bleeding, air embolism, bile leakage, tumor seeding, and fear of oncologic inadequacy and tumor spread [6, 8, 33, 34]. However, recent advances in laparoscopic techniques and instruments have led to a surge in minimally invasive approach for HCC. Several retrospective studies and literature reviews have shown the safety and feasibility of MIH for HCC [8, 9–12, 25–29, 33–35]. Furthermore, MIH seemed to be associated with faster postoperative recovery and decreased morbidity

compared with OH [25–29, 35–37]. Still, most studies were retrospective, single-institution series of a relatively small number of patients, thus resulting in limited statistical power for evaluation of outcomes. To overcome these limitations, we performed a metaanalysis comparing MIH and OH specifically for HCC. We have applied a rigorous statistical method to our literature review, with a main aim of detecting significant differences in outcomes between open and minimally invasive liver resections. Previous studies of MIH have identified a conversion rate of 5%–15%, with the most common causes being bleeding and failure to progress secondary to difficult exposure [8, 9]. The relatively low pooled conversion rate of 4% of our meta-analysis is likely a reflection of both surgeons’ expertise and selection bias; two studies only considered for MIH patients with subcapsular tumors. Moreover, the great part of MIH was carried out for HCC located in antero-lateral segments (segments 2 to 6, so-called ‘‘laparoscopic segments’’)

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FIG. 4. Funnel plots of operative outcomes. (A) Funnel plot of operative time. (B) Funnel plot of positive margins. (C) Funnel plot of intraoperative blood loss. (D) Funnel plot of transfusion rates.

[8, 38]. Subcapsular tumors located in these segments are particularly suited for laparoscopic approach because of their accessibility to laparoscopic instruments and relative distance from major biliary and vascular structures. Laparoscopic resections of HCC located in the postero-superior segments have also been described [25, 39, 40], but their safety and oncologic adequacy might need further investigations. Left lateral lobectomy is a particularly attractive procedure for a laparoscopic approach, due to the peripheral location with minimal requirement for hilar dissection and ease of controlling bleeding [9, 31, 41]. Some degree of patient selection was likely present in the studies included in our meta-analysis, as suggested by the fact that non-anatomic resections and left lateral lobectomy (segment 2 and 3) were the most common types of hepatectomy performed. Therefore, the readers should be cautious when interpreting the results of our review, which may not apply specifically for extensive liver resections. On the other hand, our results do hold validity for most of liver resections currently performed for HCC. In fact, since underlying cirrhosis usually precludes major hepatectomies, patients with centrally-located lesions are often treated

with ablative techniques, and hepatectomies larger than bi-segmentectomies are rarely performed in HCC patients. We found no significant difference in operative time between MIH and OH groups, despite different authors acknowledging longer operative times for MIH in the first part of their experience [25, 26, 29, 42]. Our meta-analysis demonstrated reduced blood loss and transfusion rates in the MIH group. This point is of particular interest, since intraoperative bleeding is one of the major concerns during laparoscopic liver resections in cirrhotic patients [8, 9, 26]. Remarkably, these results are in line with previous reviews and meta-analysis showing decreased blood loss and need for transfusion when laparoscopy is used for hepatic resections, [8–11, 36]. Limited blood loss during MIH can be obtained by maintenance of a positive abdominal pressure during parenchymal transection, and by using appropriate laparoscopic techniques (e.g., handassistance for parenchymal compression) and hemostatic devices (e.g., radio-frequency assisted resection) [25, 33, 36]. However, the difference in blood loss might have also been influenced by selection bias described above (i.e., more favorable anatomic location for MIH).

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FIG. 5. Funnel plots of postoperative outcomes. (A) Funnel plot of hospital days. (B) Funnel plot of postoperative overall morbidity. (C) Funnel plot of postoperative liver failure. (D) Funnel plot of 30-d mortality.

Selective use of Pringle maneuver is suggested for laparoscopic approach instead of routine use, even in cirrhotic patients [42]. In our analysis, the width of the resection margin between MIH and OH was not significantly different. Clearance of surgical margins is one of the main concerns in laparoscopic surgery of liver malignancies, however the margin positivity was measured differently in the papers included in our meta-analysis. Laurent and Shimada reported respectively 47.3% and 14.8% of tumors invading within 5 mm of the surgical cut surface [6, 26]. Sarpel reported 22.4% of positive margins defined as tumor invading within 3 mm of the surgical

cut surface [28]. In Belli’s experience, 4.5% of patients had margins invaded by tumor (this data was used in our analysis) and 33.5% had resection margins less than 1 cm [29]. Despite different definitions, most authors found that rates of positive margins after MIH group were lower or similar to those after OH. Accordingly, in our meta-analysis, rate of positive margins was found to be significantly lower for the MIH group. This finding could be explained by a more accurate and meticulous dissection during a laparoscopic approach or, again, just be a result of a selection bias for which tumors with favorable location were selected for laparoscopy. If further confirmed by other studies, this

TABLE 4 Comparisons of Overall and Disease-Free Survival Characteristic

No. of pooled studies

Mean MIH

Mean OH

Difference or odds ratio

0.95LLCI

0.95 UL CI

1 y OSS 2 r OSS 3 y OSS 5 y OSS 1 y DFS 2 y DFS 3 y DFS 5 y DFS

8 4 7 5 8 5 7 4

0.94 0.76 0.72 0.63 0.83 0.61 0.50 0.37

0.91 0.74 0.64 0.56 0.80 0.62 0.53 0.38

1.32 1.02 1.24 1.47 1.20 0.84 0.86 1.14

0.63 0.60 0.79 0.83 0.74 0.55 0.60 0.63

2.80 1.74 1.92 2.61 1.96 1.29 1.24 2.05

MIH ¼ minimally-invasive hepatectomy; OH ¼ open hepatectomy; OSS ¼ overall survival; DFS ¼ disease-free survival.

FANCELLU ET AL.: META-ANALYSIS OF LIVER RESECTIONS FOR HCC

finding may represent one of the strongest arguments in favor of laparoscopic approach for HCC resection. Length of hospital stay was lower for MIH. Hospital stay varied considerably across the studies included in the meta-analysis, likely because of differences in cultural and health systems across institutions from different continents [9]. The major advantages of MIH were manifest in analysis of perioperative complications: overall morbidity was lower in patients undergoing minimally invasive surgery. This is not a novel finding, as previous report comparing surgical outcomes after laparoscopic and open liver surgery have consistently shown better results with the former approach [8–10, 43]. Remarkably, our meta-analysis showed a lower rate of postoperative ascites and liver failure in the MIH group, maybe a result of decrease disruption of portosystemic shunts with laparoscopy. Given the retrospective nature of most of the studies included, patient selection (e.g., patients with higher degree of cirrhosis undergoing open procedures) might have also influenced those outcomes. The lower rates of postoperative ascites and liver failure may partially explain the lower mortality rates seen after MIH, as liver failure is a leading cause of mortality after liver resection for HCC in cirrhotic patients [8]. Preservation of collaterals with lower increase of portal hypertension may decrease postoperative ascites and digestive bleeding [44]. Other possible explanations for decreased morbidity in cirrhotic patients undergoing laparoscopic liver resection may include limited mobilization and manipulation of the liver, restricted fluid requirements and decreased blood loss, with consequently reduced thirdspace accumulation and hyperaldosteronism [6, 10, 12, 37, 45–48]. Another theoretical advantage of MIH is facilitation of eventual subsequent liver transplant because of the reduction in intra-abdominal adhesions [6, 9, 42, 49]. In our meta-analysis, 30-day mortality was lower for MIH but the difference just missed statistical significance. Our review contributes to establish that in well selected patients MIH is a safe and effective procedure. However, MIH will be accepted as a suitable alternative to OH in patients with HCC only if oncologic outcomes will be proven to be at least equal. In our meta-analysis, almost all studies reported similar survival and DFS in the two groups. The study by Laurent was the only exception, reporting a higher 3-year survival for MIH (89% versus 55%); however this difference disappeared when excluding from survival analysis the two postoperative deaths in the OH group [6]. Like any meta-analysis, our study is limited by the quality of studies included. Some degrees of selection bias were apparent in most of the studies included in

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our analysis. As mentioned above, for instance, two studied only included subcapsular tumors in the MIH group. Moreover, despite measures taken to standardize surgical population and outcome definitions, variations in inclusion criteria and operative technique between studies might have lead to differences in outcomes. Funnel plots, constructed to assess for publication bias, were symmetric for most of the outcomes and did not suggest publication bias. In contrast, the funnel plots for mortality and overall complications had few positive studies of low precision. In usual cases of publication bases, one would expect fewer negative trials of low precision. It is possible the medical centers that perform a larger volume of laparoscopic liver surgeries have fewer complications than ‘‘low volume’’ centers due to the steep learning curve for laparoscopic surgery. Further studies with a larger sample of medical centers will be needed to further confirm this possibility. A randomized controlled study of MIH versus OH for HCC would be required to overcome selection bias of currently available databases, although we should recognize that such a study would be unlikely to complete enrollment in an era when more and more patients actively seek a minimally invasive approach for their operations, and more and more surgeons offer laparoscopic liver surgery [9, 28, 33, 46, 50]. To our knowledge, only one randomized controlled trial comparing MIH and OH for HCC is under way, a study from South Korea currently recruiting participants [51]. However, results from this trial may not withhold validity for the Western countries where HCC seems to behave differently in terms of epidemiology and natural history. CONCLUSIONS

Although patient selection may have influenced some of the observed differences, our meta-analysis indicates that in carefully selected patients with HCC, MIH might be associated with improved outcomes. Compared with OH, MIH appeared to decrease blood loss, blood transfusions, overall and specific morbidity, and hospital stay, while increasing rates of negative resection margins. Overall and disease-free survival outcomes do not differ between MIH and OH, although further studies are needed to evaluate the impact of MIH on long-term results. REFERENCES 1. Hao K, Luk JM, Lee NP, Mao M, et al. Predicting prognosis in hepatocellular carcinoma after curative surgery with common clinicopathologic parameters. BMC Cancer 2009;9:389.

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