Surgical outcomes of hepatocellular carcinoma invading hepatocaval confiuence

Wei Li, Hong Wu and Jun Han

Chengdu, China

Surgical outcomes of hepatocellular carcinoma invading hepatocaval confiuence

Wei Li, Hong Wu and Jun Han

Chengdu, China

BACKGROUND: Combined liver and inferior vena cava (IVC) resection followed by IVC and/or hepatic vein reconstruction (HVR) is a curative operation for selected patients with hepatocellular carcinoma (HCC) invading the hepatocaval confluence. The present study aimed to elucidate the prognostic factors for patients with HCC invading the hepatocaval confluence.

METHODS: Forty-two consecutive patients underwent hepatectomy, combined with IVC replacement and/or HVR for HCC between January 2009 and December 2014 were included in this study. The cases were divided into three groups based on the surgical approaches of HVR: group 1 (n=13), tumor invaded the hepatocaval confluence but with one or two hepatic veins intact in the residual liver, thus only the replacement of IVC, not HVR; group 2 (n=23), the hepatic vein of the residual liver was also partially invaded, and the hepatic vein defect was repaired with patches locally; group 3 (n=6), three hepatic veins at the hepatocaval confluence were infiltrated, and the hepatic vein remnant was re-implanted onto the side of the tube graft. The patient characteristics, intra- and postoperative results, and long-term overall survival were compared among the three groups. The survival-related factors were analyzed by univariate and multivariate analysis.

RESULTS: The group 1 had higher preoperative alpha-fetoprotein level (P＜0.001), shorter operation time, hepatic ischemic time and hospital stay compared with groups 2 and 3 (P＜0.05). The 1-, 3-, and 4-year overall survival rates of group 1 were 84.6%, 23.1% and 23.1%, respectively; group 2 were 78.3%, 8.7% and 8.7% respectively and group 3 were 83.3%, 0 and 0, respectively. The multivariate analysis showed that the independent poor prognostic factors of overall survival were preoperative higher HBV DNA level (≥103copies/mL; P=0.001), tumor size (≥9 cm; P＜0.0001), age (≥60 years; P=0.010) and underwent HVR (P＜0.0001).

CONCLUSIONS: Patients with reconstructing hepatic vein with patches locally (group 2) or to the artificial graft (group 3) had worse long-term survival than those without HVR (group 1). HVR was one of the unfavorable prognostic factors of overall survival.

(Hepatobiliary Pancreat Dis Int 2016;15:593-601)

hepatocellular carcinoma;

inferior vena cava;

hepatic vein;

reconstruction

Introduction

W hen liver malignancy such as hepatocellular carcinoma (HCC) involves the major vessels including inferior vena cava (IVC) and hepatic veins adjacent to its caval confluence, combined liver and IVC resection followed by IVC and/or hepatic outflow reconstruction is a primary modality of care. A variety of surgical techniques are employed in the process of hepatectomy, vascular exclusion and vascular reconstruction. Total vascular exclusion (TVE) is the basic blood control technique which makes the procedure performed on IVC possible. If TVE is applied longer than 60 minutes, hypothermic hepatic perfusion may be necessary to acquire an extended period of time and protect the remnant liver.[1]Venovenous bypass (VVB) is needed in some TVE patients, especially when in situ perfusion technique is used.[2,3]Although it is technically challenging, we believe that combined liver and IVC resection followed by IVC and/or hepatic outflow reconstruction with synthetic or autogenous grafts is the only radical treatment that may achieve complete tumor extirpation, which offers new chances for R0 resection in otherwise unresectable cases.[4-6]

Undoubtedly, the patency of hepatic outflow was significant for the remnant liver function after hepatectomy and IVC replacement. If the hepatic vein of the residual liver was involved by the tumor, hepatic vein reconstruction (HVR) is necessary and meaningful. Different materials including allograft patches, autogenous vein patches, Dacron patchs, ePTFE (expanded polytetrafluoroethylene) patches can be applied to reconstruct the hepatic vein. The present study evaluated the outcomes of different surgical approaches. We also investigated the factors associated with overall survival of patients underwent IVC replacement and/or HVR.

Methods

Patients

We reviewed the prospectively collected data of 42 consecutive patients with HCC between January 2009 and December 2014 from a liver neoplasm database compiled by the West China Hospital, Sichuan University. The HCC diagnosis was confirmed by histology. The cases that the IVC could be sutured primarily or repaired with patches were not included in this study. Patients with R1 resection were excluded. Patients with extrahepatic diseases or other hepatic diseases were excluded. The cases were divided into three groups based on the surgical approach of HVR: group 1 (n=13), tumor invaded the hepatocaval confluence but one or two hepatic veins were not involved in the residual liver and it was not necessary to reconstruct the hepatic outflow; group 2 (n=23), tumor invasion was extended to the hepatocaval confluence of the residual liver, and the hepatic vein defect could be repaired with ePTFE patches (n=9) or autogenous vein patches (n=14); group 3 (n=6), tumor was extended to the hepatocaval confluence of the residual liver, the hepatic vein has to be reconstructed with the artificial blood vessel to replace IVC (Fig. 1). The patient characteristics, surgical procedures, postoperative morbidity and mortality, and the long-term prognosis were compared among the three groups. This study was approved by the Ethical Committee of our hospital.

Preoperative management

The hepatic vascular ultrasonography, contrastenhanced thoracic, abdominal and pelvic computed tomography (CT) and/or magnetic resonance imaging (MRI) were performed to evaluate the degree of IVC involvement and to exclude intrahepatic or extrahepatic disseminated disease. Liver function met the criteria for surgery: Child-Pugh grade A or indocyanine green retention rate at 15 minutes (ICGR15) below 10%. Preoperative portal vein embolization (PVE) was done when the anticipated liver remnant after hepatectomy was less than 50% of functional liver volume. The side of the future residual liver was drained endoscopically or percutaneously in patients with severe obstructive jaundice. Cardiopulmorary and renal function were assessed carefully to exclude the patients with contraindications for surgery. Given the high risk of the surgery and some severe complications such as liver failure and graft infection may happen postoperatively, we conducted the interventions with the consent of patients and their families.

Fig. 1. Group 1, tumor invaded the hepatocaval confluence and the hepatic vein of the residual liver is intact, thus only performing IVC replacement without HVR; group 2, the hepatic vein of the residual liver was also partially invaded, and plasty of the hepatic vein was performed with patches; group 3, three hepatic veins at the hepatocaval confluence were invaded, and the hepatic vein remnant was re-implanted onto the side of the tube graft.

Surgical procedures

Hepatectomy

Right and left (if necessary) subcostal incision with a midline extension was the most commonly used incision.“J” shaped thoracoabdominal incision was available if the right diaphragm was infiltrated by the lesions. With the cutting line confirmed by the intraoperative ultrasonography, we divided and ligated the portal pedicles of the resected side and encircled the preserved side for latter exclusion. The infra- and supra-hepatic IVC were exposed and encircled with two tourniquets (the right adrenal vein was usually ligated). Then we detached the IVC from the liver if possible. Anterior approach is advo-

cated if the lesion was huge in the right lobe of the liver. The instruments used for hepatic parenchyma transection including: Harmonic scalpel (Johnson & Johnson Corp. Princeton, NJ, USA), cavitron ultrasonic aspiration (CUSA, Valleylab Corp. Somerville, NJ, USA), and ligasure (Valleylab Corp.). The Pringle maneuver was utilized during the procedure if needed.

Vascular control technique

When dissected the critical remaining parenchyma and vascular structures, we selected different vascular exclusion techniques for resection of tumor in contact with the IVC and/or hepatic veins. We clamped the IVC below the hepatic veins on condition that there was sufficient room to place a vascular clamp above the tumor but below the hepatic vein of the remnant liver. This technique did not occlude the hepatic outflow, which is critical to reduce reperfusion injury of the liver. If the hepatocaval confluence was partially involved, we usually could not place a clamp on the portion of the IVC below the hepatic veins, then two-step vascular exclusion introduced by Azoulay et al[7]could be applied: firstly, TVE (the infra-hepatic IVC, portal triad and supra-hepatic IVC were clamped sequentially) was carried out before hepatic outflow repair (when hepatic vein of the residual liver was invaded) and IVC resection. Secondly, the hepatic outflow of the remnant liver was restored by putting the clamp below the confluence after hepatic outflow repair, IVC resection, and the upper anastomosis of the prosthetic graft. Followed by the above procedures, the hepatic inflow was unclamped and the lower cava anastomosis was completed. However, in group 3 where three hepatic veins were invaded, TVE was used until the IVC replacement and hepatic vein re-implantation were completed.

In some cases of groups 2 and 3, where TVE lasting longer than 60 minutes, in situ hypothermic hepatic perfusion solution histidine-tryptophan-ketoglutarate (HTK) (Custodial HTK; Chemie, Alsbach-Hahnlein, Germany) chilled to 4 ℃ was applied with perihepatic packing of ice.[8]After TVE being performed, the portal vein cannula was placed and the hypothermic effluent was vented from the divided hepatic vein (Fig. 2). When the hepatic vein was not divided, an incision on the cava just above the inferior IVC clamp vented the fluid. The patient’s hemodynamic condition was carefully monitored and VVB (installed from the inferior mesenteric vein, and the right femoral vein to the left internal jugular vein) was applied when the patient could not tolerate the hemodynamic fluctuation (only used in one patient).

Vascular reconstruction

Given the fact that more than 50% of the circumference of the IVC wall was involved, we replaced the IVC by ePTFE tube graft (Gore-Tex, Flagstaff, AZ, USA). If the hepatic outflow of the residual liver was not involved, only the IVC was replaced with the artificial graft. If the hepatic outflow of the residual liver was involved (three hepatic veins are all infiltrated), both of the hepatic outflow and IVC should be reconstructed with the vascular control technique demonstrated above (Fig. 1). Similarly, if less than 50% of the hepatic vein confluence was involved, the hepatic vein of the remnant liver was repaired with autogenous vein patches (the great saphenous vein which was harvested before hepatectomy was the preferable autogenous vein graft) or ePTFE patches (group 2). In group 3, the hepatic vein remnant was re-implanted onto the side of the tube graft after IVC replacement because more than 50% of the hepatic vein confluence was involved.

Fig. 2. The in situ perfusion technique. After TVE being carried out, the portal vein cannula was placed and the hypothermic effluent was vented from the divided hepatic vein.

Postoperative management

All the patients were transferred to the liver transplantation ICU in our center. The liver function and renal function were closely monitored. All patients were treated with low-molecular-weight heparin and then warfarin for 3 months with closely monitoring. Enhanced CT and/or ultrasonography were performed to observe the patency of the reconstructed IVC and hepatic veins. For HBV-related HCC, antiviral drugs were applied according to the postoperative HBV DNA level and liver function.

Postoperative mortality was defined as death during the hospital stay or within 90 days of operation. All general complications occurring at any time during the hospital stay were classified according to the Clavien-Dindo classification.[9]Liver failure was defined as peak bilirubin concentration ＞7 mg/dL, peak international normalized ratio ＞2.0, encephalopathy, or refractory ascites.[10]Bile leakage was defined as a drain fluid-to-serum total

bilirubin concentration ratio ≥3.0.[11]Renal insufficiency was defined as serum creatinine concentration above 150 μmol/L. Ascites was defined when abdominal drainage was more than 500 mL/day for longer than 3 days. Recurrence was diagnosed with CT and/or MRI during followup. The overall survival (OS) time was calculated from the date of surgery to the last follow-up or until death. The disease-free survival (DFS) time was calculated from the date of surgery to the date when the recurrence was confirmed by the imaging examination.

Statistical analysis

All analyses were performed using SPSS 17.0 statistical software (SPSS Company, Chicago, IL, USA). Continuous variables were presented as mean±SD and tested by one-way ANOVA (Student-Newman-Keuls test was used when ANOVA was significant) or presented as median (range) and tested by Kruskal-Wallis H rank test when appropriate. Categorical variables were expressed as number (%) and tested by Chi-square test or Fisher’s exact test. The OS and DFS curves were determined using the Kaplan-Meier method and compared using the log-rank test. The prognostic significance of the variables in predicting OS and DFS was performed by univariate and multivariate Cox proportional hazards regression models, and univariable and multivariable analyses were done to identify risk factors affecting patient survival. All statistical analyses were two-tailed and P values ＜0.05 were regarded as statistically significant.

Results

The demographic, clinical and surgical characteristics of the 42 consecutive patients who underwent hepatectomy, IVC replacement and/or HVR are summarized in Tables 1 and 2. The preoperative serum alpha-fetoprotein (AFP) level of group 1 was significantly higher than the other two groups (P＜0.001). The other characteristics including age, gender, numbers underwent preoperative PVE, tumor size, differentiation, clinical stage, and resection margin were similar (P＞0.05). Most of the patients were Child-Pugh class A (88.1%) and had

HBV infection (81.0%). The analysis of the intraoperative characteristics showed a significantly longer mean operative time (P＜0.001) and hepatic ischemic time (P=0.004) in groups 2 and 3. TVE was the basic blood control technique in the group 3. Two-step vascular exclusion was the most commonly used blood occlusion technique in groups 1 and 2, and the other 4 patients (30.8%) in group 1 using clamping IVC below the hepatic vein. Pringle maneuver was employed in all procedures and there was no significant difference in the three groups (P=0.757). In situ perfusion technique was more frequently used in group 3 and had a longer time than the other two groups. Meanwhile, the three groups had similar transfusion volume (P=0.221) and blood loss (P=0.086). The postoperative courses were not statistically significantly different, except for the higher serum maximum prothrombin time (PT) (P＜0.001) and longer hospital stay (P=0.024) in group 3. The frequency of postoperative complications was shown in Table 3, the difference was not statistically significant. Six patients died in 90-day after operations: liver failure in 4, respiratory complication in 1, and abdominal hemorrhage in 1.

The overall hospital mortality and morbidity were 14.3% (n=6) and 40.5% (n=17), respectively.

Table 1. Clinicopathological features of the 42 patients with HCC invading the hepatocaval confluence

Table 2. Surgical procedures and operation related parameters

Table 3. Postoperative complications

Fig. 3A is a Kaplan-Meier curve showing the OS of patients in the three groups (P=0.042). The median OS in groups 1, 2 and 3 was 27.0, 16.0 and 13.0 months, respectively. The 1-, 3-, and 4-year OS rates of group 1 were 84.6%, 23.1% and 23.1%, respectively; group 2 were 78.3%, 8.7% and 8.7%, respectively and group 3 were 83.3%, 0 and 0 respectively. The Kaplan-Meier curve showed the DFS of patients in the three groups (P=0.035, Fig. 3B). The median DFS in groups 1, 2 and 3 was 22.0, 13.0 and 10.2 months, respectively. The Kaplan-Meier curve for DFS estimated the 1-year DFS rates in groups 1, 2 and 3 were 84.6%, 39.1% and 50.0%, respectively; the 3-year were 23.1%, 4.3% and 0, respectively and the 4-year were 23.1%, 4.3% and 0, respectively. In univariate analysis for all patients, age (≥60 years; P=0.015), preoperative HBV DNA level (≥?103copies/mL; P=0.008), preoperative total bilirubin (≥?34 μmol/L; P=0.009), operative blood loss (≥800 mL; P=0.020), tumor size (≥9 cm; P=0.001), and HVR (Yes; P=0.029) were significantly associated with a worse prognosis (Table 4). The multivariate analysis showed that independent prognostic factors predicting poor survival were preoperative higher HBV DNA level (≥103copies/mL; P=0.001), tumor size (≥?9 cm; P＜0.0001), age (≥60 years; P=0.010) and HVR (Yes; P＜0.0001) (Table 5).

Fig. 3. The Kaplan-Meier survival curves showing overall survival (A) and disease-free survival (B) of patients with HCC invading the hepatocaval confluence.

Table 4. Univariate analysis of risk factors for overall survival

Table 5. Multivariate analysis of risk factors for overall survival

Discussion

When the tumor was adjacent to the hepatocaval confluence, the IVC usually needed to be reconstructed. If the hepatic vein of the residual liver was invaded, the HVR was also needed. In the present study, 42 patients with hepatectomy combined with IVC and/or HVR were included. The included criteria: the hepatocaval confluence was invaded by the tumor and the IVC was replaced with ePTFE tube graft. We excluded the patients only treated with direct suture of the IVC or hepatic vein due to the heterogeneity of surgical procedures.

The criteria of IVC reconstruction in different centers are different because of small sample size and patient heterogeneity. Like most of the centers,[7,12]we replaced the IVC with a tube graft if 50% of the IVC circumference was involved and the tumor cannot be detached from the IVC wall safely or wholly. Empirically, when more than 50% of IVC circumference was excised without IVC replacement instead of a direct suture, symptoms related to vena cava stricture such as persistent moderate leg edema developed.[6]Though many studies demonstrated that real IVC wall invasion rates were lower than that of preoperative imaging prediction,[6-8]especially in HCC. In our study, the virtual IVC wall invasion rate confirmed by pathological examination was 78.6% (data not shown), we believed that radical liver and IVC resection was necessary to achieve a tumor free margin. When the hepatic outflow of the residual liver is involved, we must reconstruct the hepatic vein, primarily repairing it with patches or reconstructing it to the ePTFE graft.[13]

Undoubtedly, when liver lesions invaded IVC and other major vessels, it was technically difficult to divide and reconstruct the vascular structures. A variety of vascular exclusion techniques, IVC reconstruction strategies, and other innovative surgical methods have brought hope for patients in this late stage.[4,5,14-18]Vascular exclusion methods, including intermittent Pringle maneuver, TVE, two-step vascular exclusion, and clamping IVC below the hepatic veins are all widely utilized in different centers.[4-8]In order to shorten ischemic time of the liver, clamping IVC below the hepatic vein (if there is room below it) and two-step vascular exclusion are two routinely used methods which significantly decrease the risk of potential ischemia-reperfusion injury of the residual liver.[7]In cases where TVE lasting longer than 60 minutes, hypothermic hepatic perfusion was applied to acquire an extended period of time and protect the remnant liver, especially in patients with cirrhosis. In the present study, in situ perfusion was mainly utilized in groups 2 and 3 since more complicated procedures were performed. Consistent with most of the reports,[2-4]we believe that VVB is necessary to cope with hemodynamic intolerance and splanchnic congestion (a decrease in mean arterial pressure ＞30% and/or a decrease in cardiac index ＞50%). Awareness and application of surgical techniques, which make it easier to remove lesions with vascular infiltration, could expand the indications for surgical excision in selected patients.

In our center, three kinds of materials were the most frequently used substitutes to reconstruct the vessels: autogenous veins (like the great saphenous vein), artificial vessels (such as ePTFE graft), and cryopreserved xenogenous vessels. Artificial vascular graft was the most commonly used material since the shortage of the xenogenous vessels and a larger surgery injury when using autogenous vein.[19,20]Though graft infection was a severe complication of artificial graft, most of the studies demonstrated that graft infection rates after artificial graft replacement was lower than 10%[6,12]and bile leakage of the cut liver surface or reconstructed bile duct was the most common complication causing graft infection. Consistent with these studies, our series showed that reconstructed vessel infection happened in two patients in group 2, eventually cured by antibiotics. However, few studies have reported the long-term outcomes of patients reconstructing major vessels with ePTFE tube graft,[21]and there was no randomized comparative trial to demonstrate which kind of the materials was better for vessel reconstruction. Though the ePTFE graft showed high patency rates in many studies, it is still necessary to monitor long-term complications of ePTFE graft used to reconstruct major vessels.

In our study, no significant difference in the shortterm survival (postoperative morbidity and 90-day mortality) was found among the three groups utilizing ePTFE tube graft to reconstruct the major vessels. However, the long-term survival showed a statistically significant difference. The group 1 (IVC replacement without HVR) had better long-term prognosis than the other two groups reconstructing both hepatic vein and IVC with ePTFE graft. The univariate and multivariate analyses also showed that having HVR performed was a factor of predicting worse survival. In group 2, venoplasty of the hepatic vein was performed with ePTFE patches or autogenous vein patches and the patients had worse longterm prognosis than group 1. When carrying out HVR, we needed a longer operation time and the liver underwent a longer ischemic time. Moreover, it resulted in more blood loss and more intraoperative blood transfusion. Given the small sample size in our study, we could not rule out type II error on short-term complications. But there may be more long-term complications associated with HVR and these complications may be related to the worse prognosis of groups 2 and 3. Except for

HVR, preoperative HBV DNA level, tumor size and age were also factors of overall mortality in the present study. Regarding HBV-related HCC, current credible evidences suggest that high preoperative serum HBV DNA concentration is a factor of poor survival after curative hepatectomy and postoperative antiviral therapy improves postoperative OS and DFS of HCC patients.[22-26]Tumor size is also identified as a risk factor for HCC recurrence and death after curative resection in many studies.[27,28]Hirokawa et al[29]demonstrated that HCC tumor size ≥5 cm is one of the significant predictors of early recurrence after hepatectomy. Huang et al[30]indicated that tumor size is the most important determinant of OS and DFS in primary stage I (American Joint Committee on Cancer staging system) HCC patients after resection. In the present study, due to the tumor was larger in these endstage patients, tumor size ≥9 cm was a statistically significant factor related to OS. Multivariate analysis showed that age was also a risk factor of mortality and patients younger than 60 years had better long-term survival. Older age was demonstrated as a factor of poor survival in many studies.[31,32]However, the prognosis of young adults with HCC is still controversial. Several studies[33,34]demonstrated that younger patients with HCC had worse prognosis than older individuals which may be due to the unfavorable clinicopathological characteristics of young patients. In the present study, patients older than 60 years was an unfavorable prognostic factor of OS.

The hepatic outflow was protected carefully during the surgery.[35]However, if the lesions involved three hepatic veins at the hepatic vein confluence, then in situ perfusion or ante-situm technique was needed to the procedure.[3,8,36]In these cases, at least one hepatic vein of the remnant liver should be reconstructed.[8,37,38]Given the severe complications of bile duct reconstruction, we did not choose ex vivo technique unless the portal structures were involved by the lesions. Instead, in situ perfusion and ante-situm technique were applied if there was not necessary to divide the portal triads.[13,39]

In conclusion, with different surgical techniques, IVC replacement and HVR can be performed safely with acceptable short-term and long-term survival in selected patients. Performing IVC replacement and HVR simultaneously will get worse long-term prognosis than only IVC replacement. The hepatic vein of the residual liver should be protected carefully during operation. According to our study, high preoperative serum HBV DNA, age, tumor size and HVR should be considered with caution. Moreover, further studies are needed to compare the surgical techniques and materials used for vessel reconstruction, thus determining the best management for these patients.

Acknowledgement: We thank Dr. Jean Thomas (Department of Liver Surgery, West China Hospital, Sichuan University) for the language revision.

Contributors: WH proposed the study. LW and HJ wrote the first draft. LW collected and analyzed the data. All authors contributed to the design and interpretation of the study and to further drafts. WH is the guarantor.

Funding: This study was supported by a grant from the Science and Technology Support Program of Sichuan Province (2014SZ0002-4). Ethical approval: This study was approved by the Ethical Committee of West China Hospital, Sichuan University.

Competing interest: No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.

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Received March 27, 2016

Accepted after revision August 22, 2016

Author Affiliations: Department of Liver Surgery & Liver Transplantation Center, West China Hospital, Sichuan University, Chengdu 610041, China (Li W and Wu H); Department of Critical Care Medicine, Sichuan Provincial Hospital for Women and Children, Chengdu 610045, China (Han J)

Hong Wu, MD, PhD, Department of Liver Surgery & Liver Transplantation Center, West China Hospital, Sichuan University, Chengdu 610041, China (Tel: +86-28-85422474; Email: Wuhong7801@163.com)

? 2016, Hepatobiliary Pancreat Dis Int. All rights reserved.

10.1016/S1499-3872(16)60152-2

Published online November 4, 2016.