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Keywords:

  • cholangiocarcinoma;
  • hilar;
  • portal vein;
  • outcome

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SOURCES
  8. REFERENCES

BACKGROUND. Surgical strategy for hilar cholangiocarcinoma often includes hepatectomy, but the role of portal vein resection (PVR) remains controversial. In this study, the authors sought to identify factors associated with outcome after surgical management of hilar cholangiocarcinoma and examined the impact of PVR on survival.

METHODS:

Three hundred five patients who underwent curative-intent surgery for hilar cholangiocarcinoma between 1984 and 2010 were identified from an international, multi-institutional database. Clinicopathologic data were evaluated using univariate and multivariate analyses.

RESULTS:

Most patients had hilar cholangiocarcinoma with tumors classified as T3/T4 (51.1%) and Bismuth-Corlette type II/III (60.9%). Resection involved extrahepatic bile duct resection (EHBR) alone (26.6%); or hepatectomy and EHBR without PVR (56.7%); or combined hepatectomy, EHBR, and PVR (16.7%). Negative resection (R0) margin status was higher among the patients who underwent hepatectomy plus EHBR (without PVR, 64.2%; with PVR, 66.7%) versus EHBR alone (54.3%; P < .001). The median number of lymph nodes assessed was higher among the patients who underwent hepatectomy plus EHBR (without PVR, 6 lymph nodes; with PVR, 4 lymph nodes) versus EHBR alone (2 lymph nodes; P < .001). The 90-day mortality rate was lower for patients who underwent EHBR alone (1.2%) compared with the rate for patients who underwent hepatectomy plus EHBR (without PVR, 10.6%, with PVR, 17.6%; P < .001). The overall 5-year survival rate was 20.2%. Factors that were associated with an adverse prognosis included lymph node metastasis (hazard ratio [HR], 1.79; P = .002) and R1 margin status (HR, 1.81; P < .001). Microscopic vascular invasion did not influence survival (HR, 1.23; P = .19). Among the patients who underwent hepatectomy plus EHBR, PVR was not associated with a worse long-term outcome (P = .76).

CONCLUSIONS:

EHBR alone was associated with a greater risk of positive surgical margins and worse lymph node clearance. The current results indicated that hepatectomy should be considered the standard treatment for hilar cholangiocarcinoma, and PVR should be undertaken when necessary to extirpate all disease. Combined hepatectomy, EHBR, and PVR can offer long-term survival in some patients with advanced hilar cholangiocarcinoma. Cancer 2012. © 2012 American Cancer Society.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SOURCES
  8. REFERENCES

Cholangiocarcinoma is a primary cancer of the bile ducts that arises from malignant transformation of the epithelial cells that line the biliary tree. Cholangiocarcinoma is a relatively rare malignancy that accounts for 3% of gastrointestinal cancers and has an annual incidence of 5000 new cases in the United States.1 Anatomically, cholangiocarcinoma can be classified into intrahepatic, distal, and hilar (Klatskin tumors) according to the location within the biliary tree.2 Up to 66% of patients with cholangiocarcinoma have a hilar tumor, usually presenting with features of biliary obstruction including jaundice.3 Although surgery offers the only potential chance at long-term survival, resection of hilar cholangiocarcinoma can be technically challenging, and only 50% to 70% of patients who undergo surgery have an attempt at curative resection.3 In addition, surgical resection often is associated with high rates of microscopically positive surgical margins.4, 5

Cholangiocarcinoma often can extend longitudinally along the hepatic ducts. Thus, the addition of hepatic resection often is necessary to obtain negative surgical margins. Resection of the extrahepatic biliary tree in conjunction with a concomitant hepatic resection has become the standard of care at major hepatobiliary centers.5-7 The role of portal vein resection (PVR) is more controversial. Although portal vein invasion traditionally has been considered a strong relative contraindication to resectability, some surgeons have advocated a more aggressive approach. Whereas several single-institutional series have been published on the topic of PVR in the management of hilar cholangiocarcinoma, the data are limited. Most series on the topic of PVR have been single-institution series that are limited by small sample sizes.8-11 In addition, reports from single institutions can be problematic, because extrapolation of such data to a wider surgical experience may not be appropriate or accurate. In the current series, we use an international, multicenter database derived from 7 major hepatobiliary centers. In the current study, we examine the short-term and long-term outcome of patients who underwent surgery to determine the effect of extent of resection on outcome. Specifically, we determine the safety and efficacy of PVR for hilar cholangiocarcinoma in a large, international, multicenter cohort of patients. In addition, we identify the factors that are predictive of long-term survival after surgery.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SOURCES
  8. REFERENCES

Patients and Data Collection

Using an international, multi-institutional database, 305 patients who underwent surgical resection of hilar cholangiocarcinoma between January 1984 and December 2010 were identified from 1 of 7 institutions (Johns Hopkins University School of Medicine, Baltimore, Md; Curry Cabral Hospital, Lisbon, Portugal; Duke Medical Center, Durham, NC; University of Virginia, Charlottesville, Va; University of Pittsburgh, Pittsburgh, Pa; Mauriziano Umberto I Hospital, Turin, Italy; and Geneva University Hospital, Geneva, Switzerland). The institutional review board of each respective institution approved the study. Only patients with histologically confirmed hilar cholangiocarcinoma who underwent surgery with curative intent at 1 of the study centers were included.

Standard demographic and clinicopathologic data were collected, including sex, age, and primary tumor characteristics. Specifically, data were collected on perioperative management, including biliary drainage, portal vein embolization, and the receipt of neoadjuvant and/or adjuvant therapy. The extent of the surgery was noted and categorized as extrahepatic bile duct resection (EHBR) only; hepatectomy plus EHBR; or combined hepatectomy, EHBR, and PVR. The extent of hepatectomy was classified as less than a hemihepatectomy, a hemihepatectomy, or an extended hepatectomy. Margin and lymph node status, the presence of perineural invasion, and American Joint Committee on Cancer stage were ascertained based on final pathologic assessment. Morbidity and perioperative mortality were recorded.12 The date of last follow-up and vital status also were collected on all patients.

Statistical Analyses

Summary statistics were obtained using established methods and are presented as percentages, mean, or median values. Overall survival was calculated from the date of surgery to the date of last follow-up. Cumulative event rates were calculated using the method of Kaplan and Meier. Univariate analyses were performed using the chi-square test or the log-rank test to compare differences between categorical groups, and the Mann-Whitney U test was used for continuous variables. After excluding postoperative deaths, Cox proportional hazards models were developed using relevant clinicopathologic variables to determine the association of each with overall survival. Relative risks were expressed as hazard ratios (HRs) with 95% confidence intervals (CIs). Significance levels were set at P < .05, and all tests were 2-sided. All statistical analyses were performed using the SPSS statistical software package (version 17.0; SPSS, Inc., Chicago, Ill).

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SOURCES
  8. REFERENCES

Patient and Tumor Characteristics

Table 1 provides the clinicopathologic features of the 305 patients who underwent curative-intent surgery for hilar cholangiocarcinoma. The mean patient age was 66 years (range, 32-86 years), and the majority of patients were men (n = 186; 70%). Most patients presented with jaundice (n = 220; 72.1%). The hilar lesion was classified as Bismuth-Corlette type I (n = 70; 23%), type II (n = 66; 21.6%), type III (n = 120; 39.3%), or type IV (n = 14; 4.6%); and 35 patients (11.5%) had an unknown Bismuth-Corlette classification. Preoperative biliary decompression was undertaken in 219 patients (71.8%; endoscopic, n = 115; percutaneous, n = 104). Twenty-four patients (7.9%) underwent preoperative portal vein embolization. Although the vast majority of patients did not receive neoadjuvant therapy (n = 287; 94.1%), a small subset did receive either neoadjuvant systemic chemotherapy (n = 8; 2.6%) or neoadjuvant chemoradiation therapy (n = 10; 3.3%). Only a minority of patients received adjuvant systemic chemotherapy (n = 65; 21.3%) or radiation therapy (n = 60; 19.7%) after undergoing surgical resection.

Table 1. Demographics of Patients With Hilar Cholangiocarcinoma (n = 305)
VariableNo. of Patients (%)
  1. Abbreviations: AJCC, American Joint Committee on Cancer.

Patient and tumor characteristics 
 Median age [range], y66 [32-86]
 Men186 (70)
 Caucasian race279 (91.5)
 Preoperative jaundice220 (72.1)
 Median tumor size [range], cm2.5 [0.3-4.0]
 Concomitant extrahepatic disease8 (2.6)
Preoperative management 
 Preoperative chemotherapy8 (2.6)
 Preoperative radiotherapy10 (3.3)
 Preoperative portal venous embolization24 (7.9)
 Preoperative biliary stenting 
  Endobiliary115 (37.7)
  Percutaneous transhepatic104 (34.1)
Operative details 
 Type of resection 
  Bile duct resection only81 (26.6)
  Bile duct resection and liver resection only173 (56.7)
  Bile duct resection, liver resection, and portal vein resection51 (16.7)
 Type of liver resection 
  <Hemihepatectomy15 (4.9)
  Right hepatectomy59 (19.3)
  Left hepatectomy82 (26.9)
  Extended right hepatectomy55 (18)
  Extended left hepatectomy13 (4.3)
 Underwent lymphadenectomy263 (86.2)
 Median no. of lymph nodes harvested [range]3 [1-22]
Pathology details 
 Resection margins 
  R0197 (64.6)
  R181 (26.6)
  R215 (4.9)
  Unknown12 (3.9)
 AJCC tumor classification 
  T1/T2142 (46.6)
  T3/T4155 (50.8)
  Unknown8 (2.6)
 Lymph node metastasis139 (45.6)
 Median no. of lymph node metastases [range]1 [0-12]
 Bismuth-Corlette classification 
  I70 (23)
  II66 (21.6)
  III120 (39.3)
  IV14 (4.6)
  Unknown35 (11.5)
 Microscopic vascular invasion97 (31.8)
 Perineural invasion195 (63.9)
 Direct invasion of liver/gallbladder/ipsilateral branches portal vein or hepatic artery123 (40.3)
 Direct invasion of main portal vein or common hepatic artery32 (10.5)
Postoperative outcome and management 
 Postoperative death 
  Within 30 d16 (5.2)
  Within 90 d36 (11.8)
 Adjuvant chemotherapy65 (21.3)
 Adjuvant radiotherapy60 (19.7)

At the time of surgery, resection involved EHBR alone (n = 81; 26.5%) or hepatectomy plus EHBR (n = 224; 73.4%). Patients underwent EHBR alone more frequently during the earlier period (1984-2000, 74.6%; 2001-2010, 26.4%), whereas most patients after 2000 routinely underwent hepatectomy plus EHBR (80.1%). Among those patients who underwent hepatectomy plus EHBR, 51 underwent a concomitant PVR (combined hepatectomy, EHBR, and PVR, n = 51; 16.7%) (Fig. 1). The extent of hepatic resection was less than a hemihepatectomy/central hepatectomy in 15 patients (4.9%), a hemihepatectomy in 141 patients (46.2%), and an extended hepatectomy in 68 patients (22.3%). Among the 51 patients who underwent PVR, 32 patients (62.7%) had disease that grossly involved the main portal vein and necessitated PVR to completely extirpate the disease, and 19 patients (37.3%) underwent a “no-touch” technique with systematic resection of the portal vein in the absence of gross involvement. Two hundred sixty-three patients (86.2%) underwent lymphadenectomy and had a median of 3 lymph nodes harvested (range, 1-22 lymph nodes harvested). On final pathologic analysis, 197 patients (64.6%) had microscopically negative surgical margins (R0); the margin status was microscopically positive (R1) in 81 patients (26.6%) and grossly/macroscopically positive (R2) in 15 patients (4.9%). Data on margin status were unavailable for 12 patients (3.9%). On final pathologic analysis, 195 patients (63.9%) had perineural invasion, whereas 139 patients (45.6%) had lymph node metastasis. Among patients who underwent PVR, pathologic microscopic or macroscopic vascular invasion was noted in 25 patients (49%) and 20 patients (39.2%), respectively.

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Figure 1. These intraoperative photographs of portal vein resection show (Top Left) dissection, (Top Right) isolation of portal structures, (Bottom Left) transection of portal vein, and (Bottom Right) reconstruction.

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Certain operative and pathologic tumor characteristics differed when we compared patients who underwent EHBR alone versus patients who underwent hepatectomy plus EHBR (Table 2). Specifically, patients who underwent a concomitant liver resection had larger tumors (median size: hepatectomy plus EHBR vs EHBR alone, 3.0 cm vs 1.5 cm, respectively; P < .001), more frequent invasion of adjacent structures (hepatectomy plus EHBR vs EHBR alone, 47.8% vs 19.8%, respectively; P < .001), and higher tumor classification (T3/T4: hepatectomy plus EHBR vs EHBR alone, 58.5% vs 29.6%, respectively; P < .001). In addition, patients who underwent hepatectomy plus EHBR were more likely to have undergone lymphadenectomy (hepatectomy plus EHBR vs EHBR alone, 89.3% vs 77.8%, respectively; P = .02). Among all patients who underwent lymphadenectomy, the overall lymph node yield was greater among patients who underwent a concomitant hepatectomy (median number of lymph nodes: hepatectomy plus EHBR vs EHBR alone, 4 lymph nodes vs 2 lymph nodes, respectively; P < .001). The ability to achieve R0 resection also was greater among patients who underwent a hepatic resection (hepatectomy plus EHBR vs EHBR alone, 66.5% vs 54.3%, respectively; P = .002). It is noteworthy that the incidence of residual gross, macroscopic (R2) disease was >5-fold higher among patients who underwent EHBR alone (12.2%) compared with those who underwent hepatectomy plus EHBR (2.2%; P = .002).

Table 2. Characteristics of Patients Undergoing Bile Duct Resection Only Versus Liver Resection (n = 305)
 Liver Resection: No. of Patients (%) 
VariableNo, n = 81Yes, n = 224P
  1. Abbreviations: AJCC, American Joint Committee on Cancer.

Patient and tumor characteristics   
 Median age [range], y69 [37-85]66 [32-86].004
 Men57 (70.4)129 (57.6).04
 Caucasian race73 (90.1)206 (91.9).61
 Preoperative jaundice12 (14.8)51 (22.8).11
 Median tumor size [range], cm1.5 [0.4-3.7]3.0 [0.3-4.0]< .001
 Concomitant extrahepatic disease0 (0)8 (3.6).12
Preoperative management   
 Preoperative chemotherapy1 (1.2)7 (3.1).69
 Preoperative radiotherapy1 (1.2)9 (4).29
 Preoperative portal venous embolization0 (0)24 (10.7).002
 Preoperative biliary stenting   
  Endobiliary27 (33.3)88 (39.3).60
  Percutaneous transhepatic30 (37)73 (32.6) 
Operative details   
 Lymphadenectomy performed63 (77.8)200 (89.3).02
 Median no. of lymph nodes harvested [range]2 [1-17]4 [1-22]< .001
Pathology details   
 Resection margins   
  R048 (54.3)149 (66.5).002
  R120 (24.7)61 (27.2) 
  R210 (12.3)5 (2.2) 
  Unknown3 (3.7)9 (4.1) 
 AJCC tumor classification   
  T1/T255 (67.9)87 (38.8)< .001
  T3/T424 (29.6)131 (58.5) 
  Unknown2 (2.5)6 (2.7) 
 Lymph node metastasis23 (28.4)116 (51.8)< .001
 Median no. of lymph node metastases [range]1 [1-4]1 [1-12].001
 Bismuth-Corlette classification   
  I43 (53.1)27 (12.1)< .001
  II24 (29.6)42 (18.7) 
  III5 (6.2)115 (51.3) 
  IV1 (1.2)13 (5.8) 
  Unknown8 (9.9)27 (12.2) 
 Microscopic vascular invasion15 (18.5)82 (36.6).03
 Perineural invasion39 (48.1)156 (69.6).06
 Direct invasion of liver/gallbladder/ipsilateral branches portal vein or hepatic artery16 (19.8)107 (47.8)< .001
 Direct invasion of main portal vein or common hepatic artery5 (6.2)27 (12.1).09
Postoperative outcome and management   
 Postoperative death   
  Within 30 d1 (1.2)15 (6.7).08
  Within 90 d1 (1.2)35 (15.6).001
 Adjuvant chemotherapy27 (33.3)38 (16.9).003
 Adjuvant radiotherapy28 (34.6)32 (14.3).001

Fifty-one patients underwent PVR, and all of those patients underwent hepatectomy plus EHBR. Among the patients who underwent PVR versus those who underwent hepatectomy alone, concomitant PVR was associated more often with a right-sided hepatectomy (combined hepatectomy, EHBR, and PVR vs hepatectomy plus EHBR, 66.7% vs 46.2%, respectively; P = .04) (Fig. 1). PVR also was associated with a greater lymph node yield (combined hepatectomy, EHBR, and PVR vs hepatectomy plus EHBR, 6 lymph nodes vs 4 lymph nodes, respectively; P = .03), but the incidence of an R0 resection was similar among patients (combined hepatectomy, EHBR, and PVR vs hepatectomy plus EHBR, 66.7% vs 64.4%, respectively; P = .67) (Table 3).

Table 3. Characteristics Comparing Patients who Underwent Hepatic Resection and Extrahepatic Bile Duct Resection Stratified According to Whether They Also Underwent Concomitant Portal Vein Resection (n = 224)
 No. of Patients (%) 
VariableBile Duct and Liver Resection Alone, |n = 173Bile Duct and Liver Resection With Portal Vein Resection, n = 51P
  1. Abbreviations: AJCC, American Joint Committee on Cancer.

Patient and tumor characteristics   
 Median age [range], y66 [32-86]66 [37-80].91
 Men100 (57.8)29 (56.9).91
 Caucasian race157 (90.8)49 (96.1).22
 Preoperative jaundice127 (73.4)29 (56.7).003
 Median tumor size [range], cm3 [0.3-14.0]2.5 [0.8-7.5].91
 Median no. of lesions [range]1 [1-5]1 [1-7].53
 Concomitant extrahepatic disease5 (2.9)3 (5.9).59
Preoperative management   
 Preoperative chemotherapy5 (2.9)2 (4).70
 Preoperative radiotherapy5 (2.9)4 (7.8).16
 Preoperative portal venous embolization16 (9.2)8 (15.7).21
 Preoperative biliary stenting   
  Endobiliary62 (35.8)26 (50.9).36
  Percutaneous transhepatic60 (34.7)14 (27.5) 
Operative details   
 Type of liver resection   
  Right-sided hepatectomy80 (46.2)34 (66.7).04
  Left-sided hepatectomy80 (46.2)15 (29.4) 
  <Hemihepatectomy13 (7.6)2 (3.9) 
 Lymphadenectomy performed153 (88.4)47 (92.2).45
 Median no. of lymph nodes harvested [range]4 [1-20]6 [1-22].03
Pathology details   
 Resection margins   
  R0115 (66.4)34 (66.7).67
  R147 (27.2)14 (27.5) 
  R23 (1.7)2 (3.9) 
  Unknown8 (4.7)1 (1.9) 
 AJCC tumor classification   
  T1/T274 (42.8)13 (25.5).02
  T3/T493 (53.8)38 (74.5) 
  Unknown6 (3.5)0 
 Lymph node disease84 (48.6)32 (62.7).36
 Median no. of lymph node metastases [range]1 [1-7]1 [1-12] 
 Bismuth-Corlette classification   
  I24 (13.9)3 (5.9).03
  II31 (17.9)11 (21.6) 
  III81 (46.8)34 (66.7) 
  IV12 (6.9)1 (1.9) 
  Unknown25 (14.5)2 (3.9) 
 Microscopic vascular invasion57 (32.9)25 (44).08
 Perineural invasion114 (65.9)42 (82.4).06
 Direct invasion of liver/gallbladder/pancreas/ipsilateral branches portal vein or hepatic artery74 (42.8)33 (64.7).004
 Direct invasion of main portal vein or common hepatic artery11 (6.4)16 (31.4)< .001
Postoperative outcome and management   
 Postoperative death   
  Within 30 d9 (5.2)6 (11.8).11
  Within 90 d26 (15)9 (17.6).65
 Adjuvant chemotherapy32 (18.5)6 (11.8).30
 Adjuvant radiotherapy30 (17.3)2 (3.9) 

Short-Term and Long-Term Outcomes

There were 16 deaths within 30 days for a 30-day perioperative mortality rate of 5.2%. Patients who underwent EHBR alone had the lowest 30-day perioperative mortality rate (1.2%); in contrast, patients who underwent a hepatectomy plus EHBR had a >4-fold increase in the risk of death within 30 days (6.7%). It is noteworthy that, among those patients who underwent liver resection, the risk of 30-day perioperative mortality was particularly pronounced in the cohort of patients who underwent concomitant PVR (combined hepatectomy, EHBR, and PVR, 11.8%; P = .03). When mortality was assessed at 90 days, the perioperative mortality rate for EHBR alone remained at 1.2%; however, the risk of death increased in the hepatectomy group to 15.6% (hepatectomy plus EHBR vs combined hepatectomy, EHBR, and PVR, 10.6% vs 17.6%, respectively; P = .16).

The 1-year, 3-year, and 5-year overall survival rates was 66.8%, 33.1%, and 20.2%, respectively (Fig. 2). On unadjusted analyses, several factors were associated with overall survival. Specifically, overall survival was worse among patients who presented with jaundice (HR, 1.48; 95% CI, 1.03-2.13; P = .04), those who had Bismuth-Corlette type III/IV lesions (HR, 1.37; 95% CI, 1.03-1.85; P = .04), and those who had evidence of perineural invasion (HR, 1.85; 95% CI, 1.32-2.61; P < .001). In addition, patients with lymph node metastasis (HR, 1.54; 95% CI, 1.17-2.04; P = .003) had a worse long-term survival (Fig. 3, top). Surgical margin status also had an impact on long-term survival (R0: referent category; R1: HR, 2.40; 95% CI, 1.76-3.28; P < .001; R2: HR, 2.70; 95% CI, 1.44-5.07; P = .002). Although patients who underwent R0 resection had a median survival of 27.7 months, the median survival for patients who underwent R1 or R2 resection was only 14.1 months and 10.3 months, respectively (Fig. 3, bottom). Whereas margin status affected overall survival, the presence of direct invasion/involvement of the portal vein did not (HR, 0.93; 95% CI, 0.57-1.51; P = .77). In addition, microscopic vascular invasion did not influence survival (HR, 1.23; 95% CI, 0.95-1.69; P = .19). Among patients who underwent hepatectomy plus EHBR, PVR also was not associated with a worse long-term outcome (HR, 0.94; 95% CI, 0.65-1.38; P = .76) (Fig. 4). The 5-year survival rate for the 32 patients who had disease that grossly involved the main portal vein and necessitated PVR (28.2%) was comparable to the 5-year survival rate for the patients who underwent a “no-touch” technique (33.2%; P = .32).

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Figure 2. Kaplan-Meier curve of overall survival for the entire cohort of patients undergoing resection of hilar cholangiocarcinoma (n = 305).

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Figure 3. These Kaplan-Meier curves of overall survival are stratified by (Top) lymph node status and (Bottom) margin status.

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Figure 4. These Kaplan-Meier curves of overall survival are stratified according to the type of operative procedure performed for hilar cholangiocarcinoma. Whereas patients who underwent extrahepatic bile duct resection alone had a worse long-term survival, patients who underwent hepatic resection had comparable long-term outcomes regardless of whether they underwent concomitant portal vein resection.

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On multivariate analyses, the only 2 factors that remained independently associated with survival were lymph node metastasis (HR, 1.79; 95% CI, 1.23-2.59; P = .002) and margin status (R0: referent category; R1: HR, 1.81; 95% CI, 1.24-2.64; P = .002; R2: HR, 3.85; 95% CI, 1.80-8.23; P < .001) (Table 4).

Table 4. Predictors of Survival in the Cohort of 305 Patients
 Univariate AnalysisMultivariate Analysis
VariableHR95% CIPHR95% CIP
  • Abbreviations: CI, confidence interval; HR, hazard ratio.

  • a

    This variable was not included in the multivariate model. Only factors that were identified as significant on univariate analysis (P < .05) were included in the multivariate model.

Men1.160.84-1.49.46aaa
Caucasian race0.810.47-1.39.43aaa
Bismuth-Corlette classification      
 I/IIReference  Reference  
 III/IV1.371.03-1.85.041.310.55-1.08.12
Preoperative portal venous embolization0.940.55-1.59.81aaa
Preoperative biliary stenting      
 NoneReference  aaa
 Endobiliary1.230.86-1.77.26aaa
 Percutaneous transhepatic1.270.89-1.82.19aaa
Preoperative jaundice1.481.03-2.13.041.500.99-2.29.06
Preoperative chemotherapy0.850.35-2.07.73aaa
Preoperative radiotherapy0.730.30-1.76.48aaa
Type of resection      
 Bile duct resection onlyReference  aaa
 Bile duct resection and liver resection0.880.64-1.20.41aaa
 No touch technique0.940.65-1.38.76aaa
Margin status      
 R0Reference  Reference  
 R12.401.76-3.28< .0011.811.24-2.64.002
 R22.701.44-5.07.0023.851.80-8.23< .001
Tumor size, cm1.020.93-1.13.68aaa
Microscopic vascular invasion1.230.95-1.69.19aaa
Perineural invasion1.851.32-2.61< .0011.400.93-2.10.10
Direct invasion of liver/gall bladder/ipsilateral branches portal vein or hepatic artery0.990.71-1.37.94aaa
Direct invasion of main portal vein or common hepatic artery0.930.57-1.51.77aaa
Concomitant extrahepatic disease0.410.15-1.10.08aaa
Adjuvant chemotherapy0.990.71-1.46.97aaa
Adjuvant radiotherapy1.100.77-1.56.66aaa
Lymph node disease1.541.17-2.04.0031.791.23-2.59.002

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SOURCES
  8. REFERENCES

The management of patients with hilar cholangiocarcinoma is complex. Patients frequently present with jaundice and elevated bilirubin, which require preoperative endoscopic or percutaneous drainage.13-15 Hilar cholangiocarcinoma also sometimes can be accompanied by lobar atrophy and a marginal size of the anticipated remnant liver, necessitating portal vein embolization.16-18 In addition, the surgical treatment of hilar cholangiocarcinoma remains one of the more technically challenging operations for hepatobiliary surgeons. Because of the complex, intimate, and sometimes variable anatomic relation of the bile duct and vascular structures, preoperative imaging can be limited in assessing vascular involvement of the tumor. Improvements in preoperative imaging with 3-dimensional computed tomography and magnetic resonance choangiopancreatography19, 20 have facilitated the preoperative determination of vascular involvement. Despite these advances, unanticipated intraoperative involvement of the portal vein still occurs with some frequency. The involvement of vascular structures by the tumor makes resection with negative margins possible only with concomitant resection of the liver and biliary tree, as well as the portal vein.10 PVR has been advocated by some as a safe treatment option for patients with hilar cholangiocarcinoma and vascular involvement.6, 8-10, 21 Management of these patients can be challenging, however, and there has been a perception that the increased technical difficulties associated with PVR lead to increased perioperative mortality. The long-term benefit of PVR also remains ill-defined. Most data on hilar cholangiocarcinoma and PVR have been single-institutional studies with limited sample size, making extrapolation and applicability of the findings difficult. The current study is important, because it reports a large, multi-institutional experience with PVR for hilar cholangiocarcinoma. The inclusion of multiple centers makes the current analysis more relevant and generalizable, because the data were derived across a broader spectrum of clinical practice. We report that PVR for hilar cholangiocarcinoma was associated with a greater risk of 30-day and 90-day perioperative mortality. We also noted, however, that PVR combined with hepatic resection provided long-term survival similar to that achieved by the patients who did not undergo PVR. In aggregate, these data strongly suggest that, although PVR may be associated with increased perioperative risk, it should be strongly considered when oncologically appropriate, because it can provide long-term outcomes comparable to the outcomes achieved among patients who require less radical resection.

A major concern around the use of PVR for hilar cholangiocarcinoma has been the perceived risk of increased morbidity and mortality. Most series report a death rate <3% to 5% for hepatic resection.22-26 Indeed, several studies have reported a perioperative mortality rate of zero,27-29 even after extended hepatic resection.30 Hepatic resection for hilar cholangiocarcinoma tends to be associated with greater perioperative mortality, with several series reporting rates in the range from 7% to 12%. Although several authors have reported no difference in perioperative mortality for patients who underwent PVR versus those who did not undergo PVR,9, 10 others have noted an increased mortality associated with concomitant PVR.8 In the current series, we report an overall 30-day mortality rate of 6.7% associated with hepatectomy plus EHBR, which is similar to other rates reported in the literature.8-10 We did note, however, that the risk of 30-day perioperative mortality was particularly pronounced in the cohort of patients who underwent concomitant PVR (hepatectomy plus EHBR plus PVR, 11.8%; P = .03). Because it has been demonstrated that reporting deaths that occur only within 30 days underestimates the mortality associated with hepatic resection,12 unlike previous studies that examined the use of PVR for hilar cholangiocarcinoma,8-10 we also evaluated 90-day mortality. Although our 30-day mortality rate was similar to the mortality reported in other studies on hilar cholangiocarcinoma,31 our data are important, because we also reported 90-day mortality. When mortality was assessed at 90 days, the perioperative mortality rate for the hepatectomy group increased to 15.6%. Perhaps more noteworthy was the finding that most of the increased mortality was attributable to the group of patients who underwent PVR (90-day mortality rate, 17.6%). These data demonstrate that, although PVR for hilar cholangiocarcinoma can be performed safely in some patients, it is associated with increased perioperative risk.

Available data on the impact of PVR on long-term survival are conflicting. Specifically, Miyazaki et al32 reported that the 5-year survival rate of the nonvascular resection group (41%) was better than that of the PVR group (25%; P < .05). Similarly, Ebata et al9 noted a worse prognosis for patients who underwent PVR versus those who did not undergo PVR (9.9% vs 36.8%; P < .001). In contrast, in more recent series, Hemming et al10 reported no difference in long-term survival between patients who underwent PVR and those who did not. Data from the current series are similar to those reported in the Hemming et al study. Specifically, although we noted that patients who underwent EHBR alone had a worse survival, patients who underwent hepatectomy with or without PVR had comparable long-term outcomes (Fig. 4). Rather, margin and lymph node status were the most important independent predictors of long-term outcome (Table 4). Specifically, R1 or R2 margin status portended a worse prognosis. Similar to other reports,5-7 we noted that the ability to achieve an R0 resection was much improved with concomitant hepatic resection. Indeed, the risk of leaving gross, residual, macroscopic disease was >5-fold greater among the patients who underwent EHBR alone compared with those who underwent hepatectomy plus EHBR. Although EHBR was practiced at some institutions early in the series, we believe that such an approach should no longer be considered both in light of previous work5-7 and based on the data presented herein. The presence of direct invasion/involvement of the portal vein or vascular invasion, however, did not influence survival. These results suggest that patients with portal vein involvement are best managed with PVR to facilitate complete extirpation of all disease to achieve negative margins.

The current study had several limitations. Despite combining the experiences of 7 major hepatobiliary centers both in the United States and in Europe, only a relatively small number of patients who underwent PVR could be identified for this study. Therefore, the current study has limited statistical power, and our statistical analyses and inferences need to be considered in light of this constraint. Another possible limitation involved our combining of patients into a composite group that underwent PVR for tumor involvement and a group that underwent PVR as a systematic, “no-touch” technique. Although some authors have advocated for a routine “no-touch” approach,6 the current study was not designed to evaluate the efficacy of the “no-touch” technique. Rather, our objective was to assess the role of PVR, as well as the safety and long-term outcomes of PVR, for patients who underwent PVR for all indications. Finally, data on the reason for postoperative mortality were not collected. Thus, we cannot comment on specific causes of death during the postoperative period. The finding that 90-day mortality was higher than 30-day mortality may suggest that mortality was related in part to liver failure, which is known as a cause of late mortality among patients who undergo major liver resection.12

In conclusion, approximately 15% of patients who underwent liver resection for hilar cholangiocarcinoma also underwent PVR. The clinicopathologic characteristics of the patients who underwent EHBR alone versus EHBR plus hepatectomy with or without PVR differed, as patients who underwent hepatectomy had larger tumors and more advanced tumor classification. Despite this difference in characteristics, the patients who underwent EHBR plus hepatectomy were more likely to achieve an R0 resection. The addition of PVR did increase perioperative mortality, but it was associated with similar long-term outcomes compared with patients who underwent hepatectomy without PVR. We conclude that hepatectomy should be considered the standard treatment of hilar cholangiocarcinoma, and PVR should be undertaken when necessary to extirpate all disease.

FUNDING SOURCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SOURCES
  8. REFERENCES

This work was supported in part by the Jill Williams Memorial Research Fund.

CONFLICT OF INTEREST DISCLOSURES

The authors made no disclosures.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SOURCES
  8. REFERENCES