Value of Live Donor Liver Transplantation Experience in Major Hepatectomy for Hepatocellular Carcinoma FREE

ALTHOUGH LIVER transplantation is an effective treatment for irreversible end-stage liver disease of various causes, it is hindered by the global shortage of cadaveric liver grafts. This shortage drives live donor liver transplantation (LDLT), an operation that addresses this need.¹ The estimate of 1% mortality of live liver donors has generated much concern.^2- 6 The cost paid by these volunteers also includes potentially serious complications such as cholestasis, biliary stricture, portal vein thrombosis,⁷ and bile leakage.⁸ In liver graft harvesting, the LDLT surgeon must achieve donor safety and good liver graft function. These goals mandate a thorough knowledge of the liver anatomy and conversance in major hepatectomy without vascular inflow clamping.

Hepatocellular carcinoma (HCC) is the most common primary liver malignancy. Although it is most prevalent in Asia and Africa,⁹ the incidence of HCC is rising in western countries.¹⁰ An HCC of larger than 5 cm is most reliably treated by tumor extirpation whenever feasible.^11- 12 During the past 3 decades, hepatectomy for HCC has evolved from a heroic and sanguinary procedure to a controlled, deliberate, and relatively bloodless operation. Nonetheless, it still poses a significant risk with a hospital mortality of 4.5%.¹¹ The risk is expected to be higher for major hepatectomy.¹³ Although survival is mainly influenced by tumor characteristics,¹⁴ treatment outcomes also depend on the surgeon's performance.¹⁵ Surgeons in our center share a common philosophy of meticulous dissection with minimal disturbance of the liver housing the HCC. This philosophy is expedited by the anterior approach for right-sided hepatectomy.¹⁶ The present study is from a tertiary referral center that provides the services of liver transplantation and the full range of hepatobiliary and pancreatic surgery. It addresses the question of whether the LDLT experience of the surgeon is a factor that influences the outcomes of major hepatectomy for HCC.

Consecutive new patients undergoing major hepatectomy for HCC from January 16, 1996, through December 28, 2001, were included in this single-center study. Major hepatectomy was defined as resection of 3 or more liver segments according to Couinaud's nomenclature.¹⁷ Selection criteria for resection included absence of extrahepatic disease and main portal vein tumor thrombus and a satisfactory liver function reserve. Data of patient characteristics, tumor characteristics, and operative findings and outcomes were collected prospectively and entered into an HCC computer database. The surgical team consisted of 7 hepatobiliary and pancreatic surgeons (HBPSs), all competent in performing major hepatectomy independently. The liver transplantation service was primarily provided by 3 of these surgeons. As dictated by the scarcity of cadaveric liver grafts in this region, LDLT was frequently performed.¹⁸ These 3 surgeons also perform regular major hepatectomies for primary and metastatic liver cancer. In this study, they were grouped as liver transplantation surgeons (LTSs). The other 4 surgeons, who were not chief LDLT surgeons, constituted the HBPS group.

Major hepatectomies were allocated to each of these 7 surgeons according to the availability of operating rooms and the predetermined operative duties of each surgeon, rather than their backgrounds or track records. All patients underwent the same preoperative evaluation protocol, which included blood biochemisty studies, percutaneous ultrasonography, and computed tomography of the abdomen. In selected patients, hepatic and superior mesenteric angiographies were performed. Liver function was assessed by means of the Child-Pugh grading¹⁹ and the indocyanine green clearance test.²⁰

Laparotomy was performed via a bilateral subcostal incision with a cephalic midline extension. Intraoperative ultrasonography was performed to determine whether the disease was operable and the extent of HCC involvement and to guide transection. The transection plane was then marked on the liver capsule by means of cautery. Hepatic parenchymal transection was performed using an ultrasonic surgical aspirator (Cavitron Ultrasonic Surgical Aspirator; Valleylab, Boulder, Colo).²¹ Venacaval branches were individually ligated or clipped and then divided. All patients received the same postoperative care by the same team of surgeons in this study. Patients were treated in the intensive care unit during the early postoperative course. Parenteral nutritional support was provided for patients with liver cirrhosis.²² Early enteric nutrition was started once bowel activity returned. Discharge from the hospital was decided according to the clinical state.

The primary end point was overall survival, calculated from the date of the major hepatectomy. The secondary end point was disease-free survival. We assessed perioperative outcomes, including blood loss, blood transfusion, and complications. The patients were followed up monthly for 6 months and then every 3 months at the outpatient clinic. Follow-up assessments included physical assessment, serum biochemistry studies, and measurement of serum α-fetoprotein level. Computed tomography was repeated every 3 months for the first 2 years and then every 6 months. Tumor recurrence was assessed on the basis of computed tomography findings and serum α-fetoprotein level.

Data were recorded prospectively in a computerized database by a single research assistant. We prospectively recorded all intraoperative and postoperative complications. Hospital death was defined as death during the hospital stay for the hepatic resection. We calculated disease-free survival from the date of hepatic resection to the date when recurrence was diagnosed. We compared groups on an intention-to-treat basis. Continuous variables were expressed as mean ± SD or median and range as appropriate. We compared categorical variables by the χ² test or the Fisher exact test, and continuous variables by means of the Mann-Whitney test. Survival analysis, including overall and disease-free survival, was estimated by the Kaplan-Meier survival method. Overall survival was calculated from the time of major hepatectomy to the date of death or the time of analysis. We analyzed statistical comparison of survival distribution by log-rank tests. Hospital death was included in the analysis of overall survival, but was excluded from the analysis of disease-free survival. We used multivariate analysis by the Cox proportional hazards regression model to identify independent prognostic factors and to predict the overall cumulative survival. We considered P<.05 to indicate statistical significance. We used SPSS for Windows, Version 10.0 (SPSS Inc, Chicago, Ill), to perform statistical analyses.

During the 6-year study period, 250 consecutive new patients underwent major hepatectomies at the Department of Surgery, The University of Hong Kong Medical Center, Queen Mary Hospital, Hong Kong, People's Republic of China. We divided the hepatectomies between the LTS (n = 102 hepatectomies) and HBPS groups (n = 148 hepatectomies). The number of major hepatectomies performed per surgeon ranged from 19 to 76. During the same period, 77 cadaveric donor liver transplantations and 107 LDLTs (89 right lobe, 3 left lobe, and 15 left lateral segment) were performed. The 2 groups were well balanced with regard to the baseline characteristics, as shown in Table 1. Most patients were male, with a mean age of 52.3 ± 2.3 and 53.5 ± 12.8 years for the LTS and HBPS groups, respectively. More than 80% of the patients had positive findings for the hepatitis B surface antigen. None of them had Child-Pugh grade C disease. The mean hemoglobin levels were within the reference range at 13.4 ± 1.7 and 13.7 ± 1.8 g/dL for the LTS and HBPS groups, respectively. The mean size of the primary liver lesion was similar (8.4 ± 4.6 and 8.3 ± 4.5 cm for the LTS and HBPS groups, respectively) (Table 2). Most livers had chronic hepatitis and cirrhosis. The extent of hepatectomy in both groups of patients is listed in Table 3. Hepatic resection appeared more extensive in the LTS than in the HBPS group, as significantly more combined segment I (caudate lobe) resections were performed (15/102 and 6/148, respectively; P = .006). Although technically demanding, segment I resection is still a safe procedure.²⁵

The intraoperative and postoperative data are listed in Table 4. Mean blood loss was less in the LTS group (1.36 ± 1.37 vs 2.21 ± 2.40 L; P<.001). Mean blood transfusion was only 0.27 ± 0.82 L in the LTS group compared with 0.51 ± 0.94 L in the HBPS group (P = .001). A smaller proportion of the LTS group required blood transfusion (17/102 [16.7%] vs 57/148 [38.5%]; P<.001). The duration of operation was comparable between the 2 groups, as were the mean tumor-free resection margins. About 5% of the patients in each group had a positive resection margin. Rupture of tumor during resection was uncommon (7.8% and 12.8% for the LTS and HBPS groups, respectively). There were 7 hospital deaths in each group (6.9% and 4.7% for the LTS group and HBPS group, respectively; P = .47). The rate of surgical complications such as bile duct injury was comparable in both groups at approximately 2%. The median hospital stay was 2 days fewer for the LTS than the HBPS groups (11 vs 13 days), although the difference was not statistically significant.

Difference in median survival was not demonstrable (45.5 and 44.7 months for the LTS and HBPS groups, respectively). The estimated 1-, 3-, and 5-year survival rates were 74.6%, 55.3%, and 44.6%, respectively for the LTS group, and 75.3%, 55.3%, and 40.9%, respectively, for the HBPS group. The median disease-free survival for the LTS and HBPS groups was 12.7 and 15.6 months, respectively. Disease-free survival at 1, 3, and 5 years was 51.6%, 34.8%, and 24.0%, respectively, for the LTS group and 55.1%, 37.3%, and 28.0%, respectively, for the HBPS group. The overall and disease-free survival rates of the 2 groups showed no statistically significant difference (Figure 1 and Figure 2).

Among the 250 patients, 74 (29.6%) required blood transfusion. There was a tendency of better overall survival in those who did not receive transfusion. The median overall survival of patients who did not have blood transfusion was 55.8 months, whereas those who had transfusion was 34.3 months (P = .06) (Figure 3). The 1-, 3-, and 5-year overall survival rates were 79.6%, 58.3%, and 48.0%, respectively, for the nontransfused group and 65.5%, 45.9%, and 33.8%, respectively, for the transfused group. The disease-free survival was also longer in the nontransfused group than in the transfused group (median survival, 16.1 vs 12.4 months), although the difference did not reach a statistical significance (P = .25) (Figure 4).

Variables that might affect the overall and disease-free survivals (ie, surgeon group, hepatitis status, cirrhosis, tumor size, vascular invasion, blood loss volume, blood transfusion, and positive resection margin) were subjected to Cox regression analysis. The hazard ratios, confidence intervals, and probability values for the multivariate model are listed in Table 5. Transfusion, cirrhosis, and venous invasion were strong independent predictors of a decreased overall survival. Venous invasion was the most significant factor, with a relative risk of 2.77. Transfusion, however, was not a risk factor in compromising disease-free survival. Venous invasion with a relative risk of 2.33 worsened disease-free survival. Cirrhosis followed by tumor size were independent predictors for poor disease-free survival. The Cox model did not show the surgeon as an independent factor that influenced survival.

Hepatic resection has been the mainstay of surgical treatment of HCC. Small HCC in a liver of poor reserve can be resected by means of a wedge excision. For unresectable small HCC (≤5 cm) in patients with decompensated Child-Pugh class B or C cirrhosis, liver transplantation is the preferred option,^26- 27 as long-term survival is offset by later deterioration of liver function and recurrent HCC.²⁸ A large HCC contraindicates liver transplantation, as the size is a strong predictor of microvascular invasion, which preludes tumor dissemination.²⁹ In the past 2 decades, suboptimal preoperative liver function, massive intraoperative bleeding, postoperative septic complications, and hepatic failure were identified as the chain of events leading to hospital death in patients undergoing hepatectomy for HCC. Therefore, we have focused on the following: (1) the preoperative evaluation of hepatic function to select patients with adequate hepatic functional reserve for hepatectomy; (2) surgical techniques to reduce intraoperative bleeding; (3) avoidance of ischemic injury to the liver remnant and biliary leakage; and (4) promotion of liver function in the postoperative period.

Live donor liver transplantation can be considered the ultimate surgery for the liver. Adult-to-adult LDLT consists of total hepatectomy for the recipient and partial hepatectomy for the donor. The latter procedure may or may not include the middle hepatic vein. Isolation and preparation of vessels of the recipient and donor require meticulous dissection and anticipation of anatomical variations. Vascular anastomosis also demands careful control of vessels. Technical difficulties at times need interpositional vascular grafts for reconstruction. Innovation and refinement in the harvesting techniques of the liver graft from the live donor were made in the past decade.^30- 32 Intraoperative ultrasonography navigates a precise line of transection.¹⁶ The exposure of the abdomen, exploration of the liver, knowledge about the tolerance of the liver for ischemia, and techniques of ex situ resection demonstrate the close ties between liver transplantation and hepatectomy.

In this study, the LTS group demonstrated better outcomes in terms of less blood loss and transfusion requirements. These are the objectives of an LDLT program that ensure the safety and well-being of the live liver donor. However, we found no difference in survival between the patients undergoing operation by the different surgeon groups. Nonetheless, survival tended to improve in those who did not receive blood transfusion. As the percentage of patients in the LTS group who underwent blood transfusion was lower than those in the HBPS group (16.7% vs 38.5%), a survival benefit in the LTS group is expected. Increased perioperative blood transfusion has been reported to increase the chance of recurrence,^33- 34 especially for large HCC.^35- 36 Reports have also shown that no association exists between blood transfusion and disease-free recurrence.^37- 38 Blood transfusion has never been reported as a factor with survival benefits, which might be the result of publication bias. Blood transfusion in this study did not emerge as a very significant factor because, unlike previous series, the volume of blood loss in this study was not large. This may be explained by the fact that the 7 surgeons were cautious and vigilant in reducing the need for blood transfusion; other nontechnical factors therefore appeared significant. This finding was reassuring, as the comparison was performed within a single center. Factors such as venous invasion and cirrhosis compromised survival at an extent that overwhelmed the effect of blood transfusion. With respect to the tumor, blood transfusion may only affect the survival of patients with early HCC who underwent hepatectomy. A study of a larger number of patients may also allow comparison between 2 groups with stratification according to each statistically significant prognostic factor.

The setup of liver surgery centers is different around the world. In European and Asian centers, a mixture of liver transplantation and hepatic resection cases is common. In the United States, centers often exclusively provide 1 of these 2 subspecialties. This brings up the issue of flexibility and diversity vs specialization, ie, would patients requiring major hepatectomy benefit from surgeons who also provide liver transplantation? This is a difficult question to answer, as studies on health care providers are often more difficult to conduct than those on health care receivers, owing to the smaller number of the former and other confounding factors such as reluctance of self-reporting. The data from the present study suggest that superspecialization in 1 particular area of liver surgery may not be desirable. Unity in hepatobiliary and pancreatic surgery with cross-fertilization between highly specialized disciplines can only benefit the patient. Versatility of surgeons also allows for a flexible service. Transplantation is often regarded as an extension of the HCC service for patients with cirrhosis or as a salvage procedure for recurrence of HCC. This setup also allows for better continuity of care.

Experience has a positive influence on the results of surgical treatment. Hence, what are the attributes of an elite hepatectomist? In a center that provides liver transplantation on an average of 1 case per week, the surgeons responsible for liver transplantation were analyzed as a single group. Their results of major hepatectomy for HCC were compared with those of the surgeons who were not intimately or ultimately responsible for patients undergoing liver transplantation. A statistically significant difference in overall and disease-free survival was not demonstrated. One could argue that the standard of service is already above the standard that might influence survival. Liver transplantation started to flourish in Asia in the early 1990s. The technical complexities and ingenuity required by the procedure allow only the most skillful surgeons to perform it. Is the selection process of surgeons or their training more crucial? Perhaps this question will never be answered, since a field trial to compare surgeons who start with hepatic resections followed by specialization in liver transplantation and those who receive training on hepatic resections only is inconceivable.

Live donor liver transplantation is built on the solid experience of major hepatic resection,³⁹ which also nurtures experience in vascular control during major hepatectomy.⁴⁰ In tandem, the 2 procedures play complementary roles in patient care. As the first of a kind, studies from centers with a similar setup can affirm this view. For centers with an established LDLT program in place, instead of gaining experience from hepatectomy for malignancies without vascular clamping,⁴¹ donor hepatectomy can be learned by assisting and operating under the guidance of experienced LDLT surgeons. As a result of the rise in the demand for LDLT, surgeons of the HBPS group in the present study have started to participate, under guidance, in LDLT as chief surgeons since early 2002, when this study was finished. A prospective examination of the results achieved by these future chimeric surgeons would be informative.

In major hepatectomy for HCC, this study did not show that the surgeon's LDLT experience has a positive influence on the overall and disease-free survival of the patients. Nonetheless, the LTS group had less blood loss and required less blood transfusion. In the 250 patients of this series, multivariate analysis showed that blood transfusion had worsened overall survival. As the blood transfusion requirement of the patients in the LTS group was significantly lower, there is a potential advantage in the overall survival.

Corresponding author and reprints: See-Ching Chan, FRACDS, FRCS(Edin), Department of Surgery, The University of Hong Kong, 102 Pokfulam Rd, Hong Kong, People's Republic of China (e-mail: seechingchan@hotmail.com).

Accepted for publication October 19, 2002.