Despite recent progress in diagnostic techniques for hepatobiliary disease, biliary tract cancer is still frequently encountered in an advanced stage.1 It has long been recognized that surgical resection with complete removal of all cancer tissues offers patients the only chance of cure and long-term survival.2,3

Hepatopancreatoduodenectomy (HPD) should be considered as the only surgery that can offer a cure for patients with diffuse bile duct cancer and advanced gallbladder cancer that has invaded the pancreatoduodenal region including peripancreatic tissue and the hepatoduodenal ligament. Hepatopancreatoduodenectomy has not been widely performed because of the associated significantly high mortality and morbidity, and the considerable surgical skill and experience necessary to surgeons who perform such aggressive surgery.4 There have been a few literature reports about HPD, and it has been reported that HPD achieved unexpectedly good results in a limited number of patients with advanced cancer of the biliary tract; 1-, 2-, and 5-year survival rates were 39.7%, 20.4%, and 6.8%, respectively, with an acceptable mortality rate of 12.5%.1 On the other hand, it has been reported that 3 of 8 patients undergoing HPD died postoperatively.4 Furthermore, in all of the literature about HPD, a high rate of severe postoperative complications (ranging from 30% to 100%) still remained a serious problem. Improvement in preoperative treatments including percutaneous transhepatic biliary drainage (PTBD) and portal venous embolization, surgical technique, and perioperative care may provide an opportunity to perform these operations in selected patients.1 In this study, we review our experience with HPD for advanced cancer of the gallbladder or the bile duct, and we seek to define the indication for HPD.

PATIENTS AND METHODS

Two-hundred nineteen patients with biliary tract cancer, including 146 cases of bile duct cancer and 73 cases of gallbladder cancer, underwent surgery at Wakayama Medical University Hospital between 1986 and 2004. Of these, 11 patients underwent HPD (5%: 6 patients with bile duct cancer and 5 with gallbladder cancer). The 11 patients with HPD included 3 men and 8 women with a mean age of 63 years (range: 50–73 years). Hepatopancreatoduodenectomy was indicated in the patients with diffuse bile duct cancer or advanced gallbladder cancer in which complete removal of the locally extended tumor and regional lymph node metastasis could be expected by performing this aggressive procedure. Tumors were staged according to the tumor node metastasis classification based on operative and histopathological findings of the resected specimen.

The maximum total bilirubin level on admission ranged from 0.2 to 29.3 mg/dl. Percutaneous transhepatic biliary drainage was performed in 8 patients with clinical jaundice. The total serum bilirubin level ranged from 1.0 to 5.7 mg/dl immediately before surgery. Right portal venous branch embolization was performed before surgery in 1 patient whose volume of the remnant left lobe was 31% and expected to increase.

Seven kinds of hepatic lobectomies or segmentectomies with simultaneous pancreatoduodenectomy were carried out in the 11 patients. Right trisegmentectomy (S5 + 8 + 6 + 7 + 4) or left trisegmentectomy (S2 + 3 + 4 + 5 + 8), and extended right (S5 + 8 + 6 + 7 + 4a) or extended left (S2 + 3 + 4 + 5) lobectomy were defined as a hepatic parenchymal resection of more than two Healey’s segments. Right lobectomy, central bisegmentectomy (S4 + 5 + 8), and segmentectomy (S4a + 5) were defined as fewer than two Healey’s segments. Biliary tract reconstruction and pancreatojejunostomy were performed with end-to-side anastomosis with a Roux-en-Y jejunal loop. Gastrojejunostomy was performed with end-to-side anastomosis at the retrocolic space. The postoperative complications, including hepatic failure and intraabdominal bleeding, were life-threatening and defined as severe complications.

Independent variables of the mortality and morbidity were analyzed by univariate methods. The statistical significance of these variables was determined by Fisher’s exact test or a chi-squared test. A P value less than 0.05 was considered to be significant.

RESULTS

Operative Findings

Intraoperative blood loss ranged from 1375 to 8400 ml, with a mean blood loss of 4116 ml in the 11 patients. The duration of operation ranged from 520 to 847 minutes, with a mean operating time of 716 minutes. A hepatic resection of the right trisegmentectomy (right lobe + medial lobe: S5 + 8 + 6 + 7 + 4) was performed in 1 patient; left trisegmentectomy (left lobe + anterior lobe: S2 + 3 + 4 + 5 + 8), in 2 patients; extended right lobectomy (right lobe + inferior part of medial lobe: S5 + 8 + 6 + 7 + S4a), in 2 patients; extended left lobectomy (left lobe + inferior part of anterior segment: S2 + 3 + 4 + S5), in 1 patient; right lobectomy, in 1 patient; central bisegmentectomy (anterior lobe + medial lobe: S5 + 8 + 4), in 1 patient; medial inferior (S4a) and anterior inferior (S5) hepatic segmentectomy, in 3 patients. The caudate lobe was removed en bloc in 7 patients with cancer involving the hepatic hilus. Pancreaticoduodenectomy (PD) was performed in 10 patients, and pylorus-preserving PD (PpPD) was accomplished in 1 patient. Combined resection of the portal vein was applied in 3 patients, and of the colon in 3 patients (Table 1).

Table 1 Operation’s Methods
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Patients with bile duct cancer included 1 with stage I, 2 with stage III, and 3 with stage IVA. The patients with gallbladder cancer included 1 with stage III and 4 with stage IVB, according to the TNM classification of the Union International Contre le Cancer (UICC; International Union Against Cancer). Specimens indicated that 2 of the 11 patients undergoing HPD had tumors at the surgical margin, at either the intrahepatic bile duct or the inferior vena cava. The remaining 9 patients had undergone curative resections with no tumors at the resection margin.

Postoperative Mortality and Morbidity

Operative deaths, defined as death within 30 days of surgery, occurred in 2 of the 11 patients (18%) (Table 2). One of these patients (No. 1) developed hepatic failure caused by anastomotic leakage in both pancreatojejunostomy and hepaticojejunostomy. Another patient (No. 2), who underwent extended right lobectomy with PD and a portal vein resection with a reconstruction using external iliac vein, developed hepatic failure caused by an obstruction of the portal vein.

Table 2 Outcome of 11 patients undergoing HPD
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Ten postoperative complications occurred in 9 (81.8%) of the 11 patients, and severe complications including hepatic failure and intra-abdominal bleeding caused by anastomotic leakage in pancreatojejunostomy and/or hepaticojejunostomy occurred in 5 patients (Table 2). Hepatic failure occurred in 4 patients, and plasma exchange was required in 3 patients. Six patients developed anastomotic leakage requiring conservative treatment. Four of the 6 leakages occurred in pancreatojejunostomy, 3 in hepaticojejunostomy, and 1 in both anastmoses. Intra-abdominal abscess requiring conservative treatment occurred in 7 patients. Delayed gastric emptying occurred in 1 patient who underwent right lobectomy with PpPD.

Table 3 lists the results of the univariate analysis of factors correlated with operative death and severe complications. The total serum bilirubin level immediately before surgery and the hepatic parenchymal resection of more than two Healey’s segments significantly correlated with an increased risk of severe complications (P = 0.0440, 0.0152, respectively). Therefore, we tried to clarify the relationship between these two factors and the postoperative complications. Table 4 shows that the hepatic parenchymal resection of more than two Healey’s segments was significantly correlated with an increased risk of hepatic failure (P = 0.0291) and anastomotic leakage in pancreatojejunostomy (P = 0.0291). Additionally, as to postoperative morbidity, a total bilirubin level of more than 3.0 mg/dl significantly correlated with an increased risk of anastomotic leakage in pancreatojejunostomy (P = 0.0440) and intra-abdominal bleeding caused by anastomotic leakage (P = 0.0386) (Table 5).

Table 3 Univariate analysis for the mortality and morbidity
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Table 4 Relationship between the volume of hepatic parenchymal resection and complications
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Table 5 Relationship between preoperative bilirubin level and complications
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Survival

The 1-, 2-, and 3-year survival rates were 44%, 33%, and 11%, respectively. Two patients with bile duct cancer died from liver metastasis 8 and 29 months after surgery. Three patients with gallbladder cancer died from liver metastasis, lymph node metastasis, and both bone and lymph node metastasis 44, 10, and 24 months after surgery. One patient (No. 10) is still alive 15 months after surgery without recurrent disease.

DISCUSSION

An extended resection including HPD is occasionally necessary as an attempt to achieve a cure in patients with biliary tract cancer. However, the indication for this extensive operation is still controversial.1,2,4,5

Our series of 11 patients with HPD demonstrated a high mortality and morbidity rate, of 18% and 82%, although the small sample size may not provide an accurate estimate of the mortality and morbidity of this aggressive surgery.

The present study showed that hepatic parenchymal resection of more than two Healey’s segments significantly correlated with the risk factor of postoperative hepatic failure and anastomotic leakage in pancreatojejunostomy. When a large amount of a normal-functioning liver is removed for a curative resection of a malignant biliary tumor, the incidence of hepatic failure may increase because of intraoperative hepatic ischemia and functioning liver damage.5 Furthermore, a depression of protein synthesis resulting from the impairment of hepatic function may increase the incidence of pancreatic anastomotic leakage after HPD.5

The purpose of portal venous embolization is to initiate compensatory hypertrophy in the remnant liver in an attempt to counteract liver failure after a major hepatectomy.3,5,6 We have not yet accumulated enough data to know whether this procedure reduces operative mortality. Actually, in this study, the remnant liver volume of one patient who underwent preoperative portal venous embolization had not increased 3 weeks later. The total bilirubin level before surgery, > 3.0 mg/dl, also correlated significantly with the risk of anastomotic leakage. It has been reported that extended right hepatic lobectomy in a cholestatic liver was one of the factors in multivariate analysis that influenced postoperative hospital mortality after radical resection for stage IV gallbladder carcinoma.7 Patients with liver damage due to obstructive jaundice are more likely to develop infectious complications than those with normal liver function. In addition, anastomotic leakage is difficult to stop in such patients, because the liver constitutes a major part of the reticuloendothelial system and plays a central role in metabolism.3

Preoperative biliary drainage remains controversial in terms of patient-benefit. Many retrospective and randomized controlled studies have concluded that preoperative PTBD does not reduce operative mortality and morbidity.1,3,5,7–11 A major disadvantage of preoperative drainage is the development of catheter-related infections. However, it has been discussed that this could be ascribed to technical inexperience.3 It is not known how long the liver has to be decompressed preoperatively by PTBD for degeneration to occur. It has been demonstrated that impaired mitochondorial function with obstructive jaundice takes a significant amount of time to improve after the relief of jaundice.12 The enhancement of liver mitochondrial function is essential to liver regeneration after hepatectomy.13 In general, the time available for decompression is limited to the minimum needed to normalize the serum bilirubin concentration. Indeed, this study has clarified that the hepatic parenchymal resection of more than two Healey’s segments and preoperative cholestatic liver were significantly correlated with an increased risk of hepatic failure and anastomotic leakage in pancreatojejunostomy. In addition, there has been a reverse in aggressiveness for this surgery during the 18 years it has been performed in our institute.

In this study, the statistical analysis showed portal vein resection was not correlated with mortality and morbidity. Resection of the portal vein with HPD remains controversial where morbidity and mortality are concerned. Some reports deny a relationship between portal vein resection and postoperative mortality.14–16

We have already demonstrated that an R0 resection by surgical procedure contributed to an improved survival rate for patients with hilar cholangiocarcinoma,17 and other groups have reported advanced cancer of the biliary tract, such as stage IV gallbladder cancer,7,18 except with peritonitis or distant metastasis.17 In the present study, the 1-, 2-, and 3-year survival rates were 44%, 33%, and 11%, suggesting that HPD offers a better chance of long-term survival by yielding a tumor-free margin, although this was a small sample. To achieve a tumor-free margin, neoadjuvant chemoradiation might be useful for downstaging, and postoperative adjuvant chemotherapy should be also considered for improvement of survival.19

In conclusion, the present study showed that hepatic parenchymal resection of more than two Healey’s segments and preoperative cholestatic liver correlated significantly with risk factors of operative death and severe complications for patients undergoing HPD. Therefore, as a better patient selection for this aggressive surgery, it might be suggested that HPD should be performed for the patients with resection of fewer than two Healey’s segments and with a total bilirubin level of less than 3.0 mg/dl by preoperative biliary drainage. However, one should consider the consequences of pushing surgical boundaries with overtly aggressive surgery of a tumor whose biology has already preset the surgical outcome.