AIM: To evaluate the clinical outcomes and safety of anterior- and conventional-approach hepatectomy for patients with large liver tumors.

METHODS: PubMed, EMBASE, Google Scholar and the Cochrane Library databases were searched for randomized controlled trials (RCTs) and controlled clinical trials comparing anterior-approach hepatectomy (AAH) and conventional-approach hepatectomy (CAH). Two observers independently extracted the data using a spreadsheet and assessed the studies for inclusion. Studies that fulfilled the inclusion criteria and addressed the clinical questions of this analysis were further assessed using either fixed effects or random effects models.

RESULTS: Two RCTs and six controlled clinical trials involving 807 patients met the predefined inclusion criteria. A total of 363 patients underwent AAH and 444 underwent CAH. Meta-analysis indicated that the AAH group had fewer requirements for transfusion (OR = 0.37, 95%CI: 0.21-0.63), less recurrence (OR = 0.57, 95%CI: 0.37-0.87), and lower mortality (OR = 0.29, 95%CI: 0.13-0.63). There were no significant differences between AAH and CAH with regard to perioperative complications (OR = 0.94, 95%CI: 0.58-1.51), intraoperative tumor rupture (OR = 0.98, 95%CI: 0.40-2.40), or length of hospital stay (weighted mean difference = -0.17, 95%CI: -2.36-2.02).

CONCLUSION: AAH has advantages of decreased transfusion, mortality and recurrence compared to CAH. It is a safe and effective method for large cancers requiring right hepatectomy.

Hepatectomy remains one of the best treatments of choice for primary or metastatic liver tumors of the right hepatic lobe. Most surgeons advise complete mobilization of the right lobe of the liver with the right hepatic vein controlled outside the liver before parenchymal transection[1]. This conventional approach hepatectomy (CAH) is considered to be effective in reducing intraoperative blood loss. However, this approach is difficult and dangerous when performing liver resection for large hepatocellular carcinoma (HCC) or for tumors with extrahepatic organ invasion in the right retrohepatic region[2]. An alternative method is anterior approach hepatectomy (AAH). This technique involves initial vascular inflow control, completion of parenchymal transection, and complete venous outflow control before the right liver is mobilized[1,3]. This approach avoids the squeezing of tumor cells into the circulation during mobilization of the tumor[4-6]. However, torrential bleeding can occur at the deeper plane of parenchymal transection from the right or middle hepatic vein. Bleeding can be substantial and difficult to control without prior mobilization of the right liver and control of the right hepatic vein[7].

With the refinement of surgical techniques and perioperative management in liver surgery during recent decades, outcomes after liver resection have improved substantially and the mortality of large hepatic resections has decreased to 3%-5%. However, safety and efficacy are still the current focus in liver resection. Many prospective randomized controlled trials (RCTs) and retrospective clinical trials have evaluated the feasibility, safety and efficacy of CAH and AAH, however, the clinical significance remains inconsistent. Currently, there are no meta-analyses available that evaluate the safety and efficacy of AAH. Therefore, we conducted a systematic review and meta-analysis to evaluate the feasibility, safety and efficacy of CAH and AAH in patients with large liver tumors in order to guide clinical practice.

For conventional hepatic resection of liver tumors, complete mobilization of the liver is necessary prior to parenchymal transection. During the course of liver mobilization, CAH can result in excessive blood loss and hemodynamic instability due to laceration of the inferior vena cava (IVC) wall, rupture or ligation slippage of the short hepatic veins. At the same time, injudicious mobilization of the liver may carry theoretical risks of prolonged ischemia of the liver remnant from rotation of the hepatoduodenal ligament, iatrogenic tumor rupture, and spillage of cancer cells into the systemic circulation[2]. These potential disadvantages of mobilization of the right liver with a large tumor using the conventional approach are well recognized. The anterior approach was first described by Ozawa, as one of the non-conventional approaches to advanced liver cancer in an attempt to avoid causing impairment. The “no-touch” isolation technique[17] has been reported to reduce intraoperative shedding of tumor cells into the portal vein during resection of colorectal cancer. However, uncontrolled massive bleeding at the deeper parenchymal transection plane is a well-known problem in AAH. To reduce the risk of bleeding from the anterior wall of the IVC and the transection surface, Belghiti et al[18] proposed the liver-hanging maneuver using a tape passed between the anterior surface of the IVC and the liver parenchyma. The liver is lifted up with a tape during parenchymal transection, and the risk of massive venous bleeding is minimized. However, there is a potential risk of bleeding from the caudate hepatic veins induced by the blind passage of an instrument anterior to the IVC. Bleeding from these branches can be substantial and difficult to stop, especially in patients with liver cirrhosis and portal hypertension[7].

Although the precise long-term prognoses in patients who undergo AAH or CAH remain unclear, many surgeons from various countries have conducted a series of controlled trials. However, any single study may be affected by potential confounding factors. Therefore, we systematically combined those related studies using meta-analysis in order to evaluate more precisely the safety and efficacy of AAH and CAH. In our study, AAH was associated with fewer transfusion requirements, mortality and recurrence after right hepatectomy. However, AAH has no advantage over CAH in relation to complications, tumor rupture and hospital stay. Our results indicate that AAH is safe and effective to reduce mortality and tumor recurrence.

Although other studies have reported that AAH has significantly less intraoperative blood loss than CAH for large tumors during right hepatectomy[3,7,12,13,15,16], our meta-analysis found no difference in blood loss between the two groups. The unavailability of blood loss data in the studies included in our meta-analysis may have contributed to this discrepancy. Therefore, studies with large samples and more RCTs are needed to resolve this conflict. The median intraoperative blood loss was lower during AAH. Consequently, the rate of perioperative blood transfusions was low. That might have led to a reduction in tumor recurrence and benefit to short-term prognosis, because excessive intraoperative bleeding has been reported to have a detrimental effect on postoperative liver function and to increase perioperative mortality[19,20].

Perioperative transfusion has also been found to promote recurrence of HCC after hepatic resection, resulting in short disease-free and overall survivals[20,21]. According to the conclusions of most of the included studies[3,7,12-16], the overall survival in the AAH group was significantly better than that of the CAH group, and the results for mortality also support this. Our meta-analysis indicated that the total complications, bile duct injury, infectious complications, and liver failure did not differ significantly between the two groups. The observation was not consistent with the suggestion by Ozawa in his initial proposal that AAH could contribute to better preservation of postoperative liver function by avoiding prolonged rotation and displacement of the hepatic lobes causing impairment of the afferent and efferent circulation of the liver remnant[2]. The studies in our analysis[1,3,7,12-16] had no uniform definition for complications, which may have influenced the results of the analysis. Thus additional studies are required to confirm the results.

The liver tumor is known to be soft, friable, and highly vascular, therefore, major right hepatectomy during difficult mobilization may result in rupture of the tumor. This usually leads to excessive bleeding and tumor cell spillage into the peritoneal cavity, and hematogenous dissemination of malignant tumor cells has been reported during surgical resection of biliary-pancreatic, colorectal and prostate cancers[3]. Modification of the surgical technique is associated with improved operative and survival outcomes of patients undergoing cancer surgery[7], hepatectomy for HCC, and surgery for other malignancies[22]. The “no-touch” isolation technique has been reported to reduce intraoperative shedding of tumor cells into the portal vein during resection of colorectal cancer[18]. This implies that the potential risk of tumor cell dissemination can theoretically be minimized with use of AAH. However, just one clinical study by Liu et al[22] reported that AAH can significantly reduce intraoperative tumor rupture, but others showed no difference. In our meta-analysis, AAH was not superior to CAH for reducing intraoperative tumor rupture. However, not all the included studies reported detailed intraoperative information. Therefore, whether tumor rupture differs significantly between the two surgical approaches should be subjected to further evaluation. Through our analysis, the incidence of extrahepatic tumor recurrence also did not differ significantly, and this result seems to support no difference in iatrogenic tumor rupture between the two groups.

In patients with liver tumors, venous permeation and vascular invasion are common. Excessive compression during mobilization may enhance the spread of tumor cells into the systemic circulation or the portal venous system. We found that tumor recurrence in the AAH group was lower than in the CAH group. Subgroup analysis found that the AAH group had less intrahepatic recurrence than the CAH group, but there was no difference in patients with both intrahepatic and extrahepatic recurrence. Thus, application of AAH in routine right hepatic resection of liver tumors influenced operative and survival outcomes, as well as recurrence of malignant tumors. However, α-fetoprotein mRNA, nucleic acid in the blood[23], and cell-free plasma albumin mRNA[24] need to be examined in follow-up clinical studies to evaluate these results further. Excessive intraoperative bleeding, perioperative transfusion and postoperative morbidity have been reported to increase perioperative mortality. Meta-analysis also verified that the AAH group had significantly less mortality than the CAH group. Thus, we found that AAH can indeed reduce tumor recurrence and improve survival outcome.

This study had a number of limitations that should be acknowledged. First, some of the trials included were RCTs while others were not, and the number of RCTs was small. Hence, the evidence from some of these studies is not of the highest possible quality. Second, there was a lack of available data on postoperative outcome, such as blood loss and tumor recurrence. Third, the heterogeneity of the patients in the included trials may have influenced the conclusions. Some trials included major and complex central liver resections, whereas others only included right hepatectomy. Most liver resections in our study were performed in HCC patients with underlying liver parenchyma damage from cirrhosis, but some were performed in normal liver parenchyma because of metastatic liver tumors. Cirrhosis is indeed recognized as a clinically relevant feature influencing morbidity and mortality after major hepatic resection[25,26]. Additionally, liver mobilization in cirrhotic patients is more technically demanding, especially in those with portal hypertension, because of a greater bleeding tendency and the presence of adhesions. Unfortunately, the included trials did not provide detailed data regarding cirrhosis, thus, we could not conduct a subgroup analysis between patients with and without cirrhosis.

In conclusion, patients in the AAH group had fewer transfusion requirements, tumor recurrences and reduced mortality compared to those in the CAH group. However, the anterior approach had no advantages over the conventional approach in relation to blood loss, morbidity or hospital stay after right hepatectomy. The current evidence from the available clinical trials demonstrated that AAH is a safe and effective method of liver resection for large tumors needing right hepatectomy. However, further well-designed, multicenter trials are needed to evaluate the role of AAH.