 |
|
Major Hepatic Resection for Hilar Cholangiocarcinoma
Analysis of 46 Patients
David J. Rea, MD;
Manuel Munoz-Juarez, MD;
Michael B. Farnell, MD;
John H. Donohue, MD;
Florencia G. Que, MD;
Brian Crownhart, BS;
Dirk Larson, MS;
David M. Nagorney, MD
Arch Surg. 2004;139:514-525.
ABSTRACT
| |
Hypothesis Major hepatectomy, bile duct resection, and regional lymphadenectomy for hilar cholangiocarcinoma are associated with actual long-term (>5 years) survival.
Design Retrospective outcome study.
Setting Single tertiary referral institution.
Patients Between 1979 and 1997, 46 consecutive patients had resection of hilar cholangiocarcinoma by major hepatectomy, bile duct resection, and regional lymphadenectomy.
Main Outcome Measures Overall survival and tumor recurrence were correlated to clinicopathological factors, operative morbidity, and mortality.
Results Twenty-five patients underwent left hepatectomy, 17 underwent right hepatectomy, and 4 had extended right hepatectomy. Eighteen patients underwent resection of segment 1. Negative (R0) resection margins were achieved in 37 patients (80%). The operative mortality rate was 9%, and the surgical morbidity rate was 52%. Actual 1-year, 3-year, and 5-year survival rates were 80%, 39%, and 26%, respectively. Factors adversely associated with patient survival rates included: male sex, lymph node metastases, tumor grade 3 or 4, elevated direct serum bilirubin level at diagnosis, elevated preoperative activated partial thromboplastin time, and more than 4 U of red blood cells transfused perioperatively. Tumor size and R0 resection approached significance for survival. Factors associated with tumor recurrence included: male sex, tumor grade 3 or 4, a low hemoglobin level both at diagnosis and preoperatively, and a low preoperative prothrombin time and low alkaline phosphatase level at diagnosis and preoperatively. Median time to recurrence was 3.6 years. Tumor recurrence was predominantly local and regional.
Conclusions The actual 5-year survival rate of 26% justifies major partial hepatectomy, bile duct resection, and regional lymphadenectomy for hilar cholangiocarcinoma. The high frequency of local and regional recurrence warrants investigation of adjuvant therapy.
INTRODUCTION
Since the reported resection of a primary cancer originating at the hepatic duct confluence by Brown and Myers1 in 1954, hilar cholangiocarcinoma (HC) has remained a formidable challenge. Early independent descriptions of the major clinical and pathological features of HC highlighted the management problems posed by this malignancy.2-3 These clinical and pathological features, along with more recent molecular aspects of biliary tract cancers, have recently been reviewed by our institution.4 Despite a reputed slow tumor growth rate and uncommon hematogenous metastases, the propensity for extensive local invasion of the hepatic hilum and the limited resolution of hepatic hilar imaging initially accounted for the low overall resectability. As a consequence of limited resectability of HC, prognosis was poor and surgical management was primarily palliative. In fact, early attempts at complete resection were noteworthy.5
In 1979, the first substantive experience of patients undergoing resection for HC was reported.6 With improved resolution of hepatic hilar imaging and further recognition of the patterns of HC growth, operative approaches for resection of HC have evolved. The inclusion of partial hepatectomy of variable extent to address both direct hepatic invasion and the intrahepatic intraductal extension of HC has been the major advance in the surgical management of HC during the last 2 decades.7-8 Subsequently, numerous investigators have demonstrated that complete resection of HC inclusive of partial hepatectomy and regional lymphadenectomy may be the operative treatment of choice for select patients.9-13 Despite promising survival outcomes, perioperative mortality and morbidity remain formidable. Although recent single and multi-institutional reports have endorsed major partial hepatectomy, bile duct resection, regional lymphadenectomy, and Roux-en-Y hepaticojejunostomy for HC, actual 5-year follow-up is sparse.14-15 These considerations prompted our review of this operative approach for HC at the Mayo Clinic, Rochester, Minn, during the last 2 decades. Our aims were to reexamine the clinical and pathological features of HC, to correlate these factors with patient survival rates and tumor recurrence, and to define the actual long-term (5-year) survival associated with this operative approach.
METHODS
This study was performed with approval by the Mayo Foundation institutional review board. We reviewed the records of consecutive patients with HC who underwent major partial hepatic resection, resection of the extrahepatic bile duct to the head of the pancreas, removal of the gallbladder (if present), regional lymphadenectomy, and Roux-en-Y hepaticojejunostomy at the Mayo Clinic from 1979 to 1997. We limited our study through 1997 to obtain a minimum potential follow-up interval of 5 years. Data were abstracted from institutional medical, surgical, and pathological records and from available extrainstitutional records. Clinical features at initial examination and comorbid conditions were recorded. The Eastern Cooperative Oncology Group scale16 was used to categorize patient performance status before and after surgery. The assessment of proximal and distal tumor extent in the biliary tree was estimated preoperatively with endoscopic retrograde cholangiography and/or percutaneous transhepatic cholangiography. Preoperative biliary decompression, whether endoscopic or transhepatic, was recorded. Ultrasonography and computed tomography were used preoperatively to evaluate local and distant tumor involvement. Visceral angiography was used selectively to define regional vascular invasion. Laboratory data at diagnosis and immediately prior to operation (preoperative) included the following: platelet count; levels of hemoglobin, serum calcium, serum phosphorus, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, total bilirubin, direct bilirubin, total protein, and albumin; prothrombin time; and activated partial thromboplastin time. Adenocarcinoma of bile duct origin was confirmed histopathologically in each patient. Pathological factors examined included: tumor size, tumor grade, lymph node metastases, and margins of resection. Tumor grading was according to the method of Broder. The American Joint Committee on Cancer 200217 was used for tumor staging. The anatomical extent of bile duct involvement was typed by the classification of Bismuth and Corlette.18 Resection was considered as curative in intent if all gross cancer was excised and microscopic margins of resection were tumor free. Major partial hepatic resection was defined as resection of 3 or more anatomical hepatic segments. Regional lymphadenectomy was defined as excision of hilar, cystic, pericholedochal, posterior-superior pancreaticoduodenal, portal, and hepatic arterial lymph nodes. Portal venous resection was either segmental or tangential. Operative mortality was defined as death within 30 days of surgery or during hospitalization of the index operation. Any events prolonging or complicating patient recovery were classified as operative morbidity.
All continuous variables are reported as the mean ± standard deviation. Survival and recurrence rates were calculated using the Kaplan-Meier method.19 Comparisons of discrete variables in the Kaplan-Meier analyses were made using log-rank tests.20 The effects of continuous variables on these outcomes were evaluated using Cox proportional hazards models.21 Potential predictors of survival and tumor recurrence were evaluated in multivariable Cox proportional hazards models. Beginning with a pool of clinically important factors and statistically significant predictors identified in the univariate analyses, variables were selected using stepwise regression. The resulting models were validated using a bootstrap resampling technique with 500 iterations.22 Variables that were significant in at least 60% of the 500 bootstrap samples were included in the final models. P values <.05 were considered statistically significant. All analysis was conducted using SAS version 8.2 (SAS Institute Inc, Cary, NC) on a Sun Ultra II computer (Sun Microsystems Inc, Palo Alto, Calif).
RESULTS
Forty-six consecutive patients underwent major partial hepatic resection, resection of the extrahepatic bile duct to the head of the pancreas, removal of the gallbladder (if present), regional lymphadenectomy, and Roux-en-Y hepaticojejunostomy for HC during the study period. Demographics and clinical findings of our patients are presented in Table 1. There were 25 men and 21 women with a mean ± SD age of 59.7 ± 11.3 years (range, 36-86 years). The mean ± SD duration of symptoms was 2.9 ± 4.6 months (range, 0-24 months). Symptoms included weight loss (29 patients [63%]), pruritis (27 patients [59%]), anorexia (22 patients [48%]), pain (21 patients [46%]), and fatigue (19 patients [41%]). The mean ± SD weight loss at diagnosis was 4.2 ± 4.1 kg (range, 0-15 kg). Physical signs at the time of diagnosis included jaundice (37 patients [80%]), hepatomegaly (14 patients [30%]), fever (5 patients [11%]), and cachexia (3 patients [7%]). Only 1 patient had an abdominal mass. Despite these symptoms, the preoperative Eastern Cooperative Oncology Group scale status of patients was 0 in 35 patients (76%), 1 in 6 (13%), and 2 in 5 (11%). Medical history of our patients included the following: a history of liver or biliary tract disease in 10 patients (22%), hypertension in 10 (22%), hepatitis in 6 (13%), other malignancy in 5 (11%), and diabetes mellitus in 3 (7%). Prior biliary tract disease consisted of a prior cholecystectomy for acute or chronic cholecystitis (with or without cholelithiasis) in nearly all patients. Two patients had primary sclerosing cholangitis. Prior malignancies included either squamous cell cancer of the skin or breast cancer.
|
|
|
|
Table 1. Demographics, Clinical Features, Functional Status, and Comorbidities of Patients Undergoing Major Hepatic Resection for Hilar Cholangiocarcinoma*
|
|
|
Diagnostic imaging was not standardized across the study period because of the duration of the study period and both the evolution of imaging modalities and the sequence of imaging obtained. The biliary tract was evaluated by percutaneous transhepatic cholangiography in 37 patients (80%) and by endoscopic retrograde cholangiography in 38 patients (83%). All patients had cholangiographic findings consistent with malignancy. Ninety-six percent of patients (44 of 46) underwent computed tomography. Five patients (11%) had their scan results interpreted as normal. Ultrasonography was used in 37 patients (80%), and results were interpreted as negative for tumor in 6 patients (16%). Visceral angiography was used preoperatively in 37 patients (80%), and results were interpreted as normal in 16 patients (43%). More recently, visceral angiography has been supplanted by computed tomographic angiography and high-resolution Doppler ultrasonography of the hilar vasculature. Preoperative biliary drainage was performed in 35 patients (76%). Biliary tract decompression was performed at the discretion of the interventional radiologist, endoscopist, or surgeon and was not standardized preoperatively.
We classified HC cholangiographically as Bismuth type II in 7 patients (15%), type IIIa in 18 patients (39%), and type IIIb in 21 patients (46%). Patients with Bismuth type II HC required lobectomy because of direct parenchymal invasion or invasion of the lobar vasculature. Seventeen patients (37%) underwent right hepatic lobectomy (segments 5-8), 25 patients (54%) underwent left lobectomy (segments 2-4), and 4 (9%) underwent extended right lobectomy (segments 4-8). Of the 46 patients undergoing resection, 18 (39%) had concomitant caudate lobe (segment 1) resection. The pathological data from our series are shown in Table 2. Margins of resection were negative (R0 resection) in 37 patients (80%); microscopically positive (R1 resection) in 5 patients (11%); and grossly positive (R2 resection) in 4 patients (9%). All patients with caudate lobe resections had negative surgical margins. Direct tumor extension into the liver occurred in 20 patients (43%). Extension of HC into the ducts of the caudate lobe was documented pathologically in 9 (50%) of 18 patients. Portal vein invasion was documented pathologically in 15 patients (33%). Hepatic artery involvement was less common, occurring in only 5 patients (11%). Vascular involvement was always ipsilateral to the resected liver.
|
|
|
|
Table 2. Pathological Findings and TMN Stage of Hilar Cholangiocarcinoma in Patients Undergoing Major Hepatic Resection*
|
|
|
The mean ± SD operative time was 5.8 ± 1.3 hours. The hepaticojejunostomy was intubated intraoperatively in 44 patients (96%) and intubation was transhepatic in 39 (85%) of these patients. Thirty-three patients required intraoperative red blood cell transfusions, with a mean ± SD transfusion requirement of 4 ± 5 U. The mean ± SD number of red blood cell units transfused during the hospitalization was 6 ± 7 (range, 0-33 units). The patient operative mortality rate was 9% (4/46). The causes of death were gastrointestinal tract hemorrhage from a postoperative pancreatic abscess, ischemic liver failure in 2 patients (1 from a hepatic arterial thrombosis and 1 from a portal vein thrombosis), and multiorgan failure from sepsis.
Serious operative morbidity occurred in 24 patients (52%). Complications included transient liver failure in 5 patients (11%), perihepatic abscess in 5 (11%), cholangitis in 3 (7%), wound infection in 3 (7%), biliary leak in 2 (4%), gastric outlet obstruction in 2 (4%), respiratory failure in 2 (4%), and upper gastrointestinal tract bleeding in 2 (4%). A hepatic abscess, pancreatitis, congestive heart failure exacerbation, myocardial infarction, aspiration pneumonia, leakage from the hepaticojejunostomy, vocal cord paralysis, and Clostridium difficile colitis each occurred in 1 patient. Some patients had multiple complications. Infectious complications did not differ between patients who had or did not have preoperative biliary decompression.
The overall median survival was 2.3 years and the actual 5-year survival rate was 26% (Figure 1, A). Currently 7 (15%) of 46 patients are alive. Median time from the date of operation to last follow-up for the actual survivors was 6.4 years with the longest follow-up 14.0 years. The 1-year and 5-year survival rates for patients with curative (R0) resections were 84% and 30%, respectively. The correlation of clinical and pathological factors to survival is presented in Table 3. Male sex (P = .003), lymph node metastases (P = .04), tumor grade 3 or 4 (P = .03), elevated direct bilirubin level at diagnosis (P = .001), elevated activated partial thromboplastin time value (P = .04), and more than 6 U of red blood cells transfused perioperatively (P = .001) were statistically significant for poor overall survival. Survival of patients by TNM stage (American Joint Committee on Cancer 2002) was also significant (P = .04) (Figure 1, B). The most robust difference in survival was noted between patients with American Joint Committee on Cancer 2002 stage IA and IB HC and those with stage IIB HC (P = .009). R0 resections (Figure 1, C) and tumor size less than 3 cm approached significance for improved survival (P = .06 and P = .10, respectively). Adjuvant treatment with chemotherapy, irradiation, or both and resection of the caudate lobe did not affect overall survival.
|
|
|
|
A, Overall Kaplan-Meier19 survival rate for all patients undergoing major hepatectomy, bile duct resection, and regional lymphadenectomy. The median survival is 2.3 years, and the 5-year survival rate is 26%. B, Kaplan-Meier survival rate by American Joint Committee on Cancer 2002 stage17. The survival difference among all groups is statistically significant (P = .04). C, Kaplan-Meier survival rate for patients undergoing R0 resection (negative margins) vs R1 and R2 resections (positive margins). The difference in survival approached statistical significance (P = .058).
|
|
|
|
|
|
|
Table 3. Correlation of Clinical and Pathological Factors to Survival in Patients With Hilar Cholangiocarcinoma Undergoing Major Hepatic Resection
|
|
|
We documented HC recurrence in 19 (50%) of 38 patients with a median recurrence time of 3.6 years. The longest interval to recurrence was 5.3 years. The primary site of recurrence was the liver in 10 (53%) of 19 patients, the peritoneum in 5 (26%), biliary tract in 4 (21%), retroperitoneum in 3 (17%), and lungs in 1 (5%). Recurrence in the liver was typically adjacent to the resection interface. Some patients had multiple sites of recurrence. No recurrence was considered operable with intent for cure. We performed an analysis of variables associated with tumor recurrence, which is presented in Table 4. By univariate analysis, an increased rate of tumor recurrence was associated with male sex (P = .02), tumor grade 3 or 4 (P = .005), a low hemoglobin level at diagnosis and preoperatively (P = .01 and P = .03, respectively), a low preoperative prothrombin time (P = .01), and a low alkaline phosphatase level at diagnosis and preoperatively (P = .004 and P = .03, respectively). R0 resection and the absence of lymph node metastases approached significance for recurrence-free survival (P = .19 and P = .16, respectively). Adjuvant chemotherapy and caudate lobe resection were not associated with the frequency of recurrence.
|
|
|
|
Table 4. Correlation of Clinical and Pathological Factors to Recurrence in Patients With Hilar Cholangiocarcinoma Undergoing Major Hepatic Resection*
|
|
|
A stepwise regression model was used to further correlate significant univariate factors to survival and tumor recurrence. In the multivariable analysis for survival, we included age, sex, a history of hepatitis, tumor grade, lymph node metastases, margin status, tumor size, TNM stage, direct bilirubin level at diagnosis, and number of units of red blood cells transfused perioperatively. Identical variables, including the prothrombin time, were used in the multivariable analysis for recurrence. The results of the multivariable analysis for survival and recurrence are presented in Table 5. By the multivariable analysis, history of hepatitis, male sex, a high direct bilirubin level at diagnosis, and more than 4 U of red blood cells transfused perioperatively were significantly associated with poorer survival. In contrast, only high tumor grade was significantly associated with increased recurrence rate. When these models were validated using the bootstrap technique, the variables that were validated in our model included only male sex and the number of units of red blood cells transfused perioperatively for overall survival and tumor grade for recurrence.
|
|
|
|
Table 5. Multivariable Analysis of Predictors for Patient Survival and Tumor Recurrence
|
|
|
COMMENT
The major findings of our study of patients with HC undergoing hepatic and biliary tract resection and regional lymphadenectomy with Roux-en-Y hepaticojejunostomy were that the actual survival rate of patients at 5 years was 26% and that few clinicopathological factors were associated with survival. Our findings provide further support for this operative approach for HC recommended by others based on actuarial 5-year outcome.23-27 Although few clinicopathological factors herein were associated with survival, our study supports the finding of others identifying tumor stage and grade and resection margins as significant associations with survival.12-15,23-27 The frequency of recurrence was significant and clearly dictates investigation of adjuvant treatment strategies.
The actual 5-year survival rate for patients undergoing resection of HC by partial major hepatectomy, bile duct resection, and regional lymphadenectomy was 26%. These findings are consistent with the predicted 5-year survival rate ranging from 29% to 40% reported by others performing similar operations during concurrent time periods.12-15,23-27 Similarly, our operative mortality and morbidity rates of 9% and 52%, respectively, are comparable with others who have reported perioperative mortality rates ranging from 0% to 14% and perioperative morbidity rates from 14% to 64%.12-15,23-27 Although our perioperative risk decreased across the study period, our findings clearly show that the risk of resection is still significant. These findings, coupled with the reports of reduced risk from centers with special interest in HC and the low overall incidence of HC, support the referral of such patients to tertiary centers for operative management.
Two approaches have been proposed recently to reduce the perioperative risk of partial hepatectomy for HC: (1) preoperative biliary drainage of the anticipated hepatic remnant and (2) preoperative portal vein embolization (PVE) of the anticipated hepatic resection. Internal biliary drainage restores bilioenteric flow, which improves hepatic function, decreases the adverse systemic effects of cholestasis, and may decrease the risk of sepsis by restoration of the enterohepatic circulation of endotoxin-binding bile salts. With complete relief of jaundice by drainage, postoperative liver failure has been less than 10% and infectious complications were not increased.27-29 Although most of our patients had preoperative biliary drainage, which was not applied in a standardized fashion, a lower total bilirubin level preoperatively was associated with improved survival. We have had no experience with PVE for HC. The rationale for PVE is to induce hypertrophy of the hepatic remnant thereby improving hepatic function and decreasing the risk of postoperative liver failure. Portal vein embolization is not indicated in the presence of an atrophy-hypertrophy complex associated with HC. Several recent reports suggest benefit with a decrease in postoperative liver failure to only 2% after resection of HC.27, 29 To date, PVE has usually been used with concurrent biliary drainage and whether drainage or PVE more significantly influences outcome is unknown. Further investigations of these modalities to reduce perioperative risk seem warranted.
We limited our study to patients undergoing major hepatic resection for HC. Although HC may be resected with curative intent without partial hepatectomy or with minor hepatectomy (<3 segments), intrahepatic biliary extension, direct hepatic parenchymal invasion at the hilar plate, unilobar vascular involvement, and the atrophy-hypertrophy complex more frequently dictate concurrent major hepatectomy for tumor clearance. The small number of patients accrued in our study period reflects our concern in weighing the perioperative risk against the limited survival rate expected for patients with incomplete resection, which occurs not infrequently. Indeed, despite improved resolution of most imaging modalities used to assess resectability of HC and staging laparoscopy, selection of patients for R0 resections remains imprecise.30 Overall resectability rates currently range from 20% to 80%, and 10% to 50% of resections are R1.12-15,23-27 Although median survival after R1 resection was 20 months herein, survival of patients after R1 resections of HC have ranged from 11 to 24 months elsewhere.12-15,23-27 Until prospective quality of life data after R1 resection of HC support its efficacy, we believe that our current conservative position of careful selection of patients for operative management of HC is tenable.
Numerous studies have correlated various clinical and pathological factors with survival of patients with HC after resection. Cumulative evidence strongly supports hepatic resection as a significant predictor of survival. Additionally, low tumor stage, absence of lymph node metastases, R0 resection, caudate lobe resection, and the absence of lobar atrophy have been associated with an increase in survival.24-31 Our findings are consistent with these reports and further showed that tumor grade was associated with survival. The association of sex with patient survival has previously been reported, but an association of prior hepatitis and volume of perioperative transfusion with poor survival has not been reported for HC. Although female sex was associated with prolonged survival, we are unaware of a cause of this association by hormonal responsiveness of this cancer. The perioperative transfusion is likely a surrogate marker for a complex hospital course and our 4 operative deaths had large transfusion requirements. Previous history of hepatitis (viral type unknown) may reflect both inadequate regenerative and functional capacity. The association of low serum alkaline phosphatase levels and greater tumor recurrence may be a statistically significant association without clinical importance. Although low serum alkaline phosphatase levels may be the result of a more dysplastic epithelium or even occult carcinoma in situ, we have not corroborated those histologic findings with the serum levels herein.
We do support the role of caudate lobectomy as an integral component of partial hepatectomy for HC despite our lack of correlation with survival because of the clinically occult but pathologically recognized extension into the caudate lobe ducts.29, 31 In contrast, we infrequently incorporate resection of all of segment 4 with right hepatectomy (segments 5-8) but extend the resection nonanatomically into segment 4B to provide an adequate parenchymal margin around the hilar plate because segment 4 ducts seldom arise directly anterior from the main left duct. Finally, we have been reluctant to incorporate portal venous resection and reconstruction into our practice because of the associated mortality and morbidity and limited long-term survival.7, 29
Despite the relatively high complication and mortality rates for resection of HC compared with other hepatic tumors, the 26% 5-year survival rate is comparable to that of primary and metastatic cancer to the liver. However, the high local and regional failure rates and overall survival rate support the investigation of adjuvant therapies. Both systemic and local-regional modalities such as intraoperative radiation, brachytherapy, and photodynamic therapy warrant multi-institutional review.32-33 For those patients with locally unresectable HC, recent results with aggressive neoadjuvant chemoirradiation and liver transplantation offer hope to highly select patients.34-35
AUTHOR INFORMATION
Corresponding author: David M. Nagorney, MD, Department of Surgery, Division of Gastroenterologic Surgery, Mayo Clinic College of Medicine, 200 First St SW, Rochester, MN 55905 (e-mail: nagorney.david{at}mayo.edu).
Accepted for publication January 22, 2004.
This study was presented at the Scientific Session of the Western Surgical Association; November 11, 2003; Tucson, Ariz; and is published after peer review and revision. The discussions that follow this article are based on the originally submitted manuscript and not the revised manuscript.
From the Department of Surgery, Divisions of Gastroenterologic and General Surgery (Drs Rea, Munoz-Juarez, Farnell, Donohue, Que, and Nagorney) and Biostatistics (Messrs Crownhart and Larson), Mayo Clinic College of Medicine, Rochester, Minn.
REFERENCES
1. Brown G, Myers N. The hepatic ducts: a surgical approach for resection of tumour. Aust N Z J Surg. 1954;23:308-312.
PUBMED
2. Altemeier WA, Gall EA, Zinninger MM, Hoxworth PI. Sclerosing carcinoma of the major intrahepatic bile ducts. Arch Surg. 1957;75:450-461.
3. Klatskin G. Adenocarcinoma of the hepatic duct at its bifurcation within the porta hepatis. Am J Med. 1965;38:241-256.
FULL TEXT
|
ISI
| PUBMED
4. De Groen PC, Gores GJ, LaRusso NF, Gunderson LL, Nagorney DM. Biliary tract cancers. New Eng J Med. 1999;341:1368-1378.
FREE FULL TEXT
5. Sanguily J, Calderin VO. Partial resection of the liver for primary cholangiocarcinoma: presentation of a successful case. Am J Surg. 1974;128:603-607.
FULL TEXT
|
ISI
| PUBMED
6. Launois B, Campion JP, Brissot P, Gosselin M. Carcinoma of the hepatic hilus: surgical management and the case for resection. Ann Surg. 1979;190:151-157.
ISI
| PUBMED
7. Nimura Y, Hayakawa N, Kamiya J, et al. Combined portal vein and liver resection for carcinoma of the biliary tract. Br J Surg. 1991;78:727-731.
ISI
| PUBMED
8. Sugiura Y, Nakamura S, Iida S, et al. Extensive resection of the bile ducts combined with liver resection for cancer of the main hepatic duct junction: a cooperative study of the Keio Bile Duct Cancer Study Group. Surgery. 1994;115:445-451.
ISI
| PUBMED
9. Kosuge T, Yamamoto J, Shimada K, Yamasaki S, Makuuchi M. Improved surgical results for hilar cholangiocarcinoma with procedures including major hepatic resection. Ann Surg. 1999;230:663-671.
FULL TEXT
|
ISI
| PUBMED
10. Klempnauer J, Ridder GJ, von Wasielewski R, Werner M, Weimann A, Pichlmayr R. Resectional surgery of hilar cholangiocarcinoma: a multivariate analysis of prognostic factors. J Clin Oncol. 1997;15:947-954.
FREE FULL TEXT
11. Jarnagin WR, Fong Y, DeMatteo RP, et al. Staging, resectability, and outcome in 225 patients with hilar cholangiocarcinoma. Ann Surg. 2001;234:507-517.
FULL TEXT
|
ISI
| PUBMED
12. Su CH, Tsay SH, Wu CC, et al. Factors influencing postoperative morbidity, mortality, and survival after resection for hilar cholangiocarcinoma. Ann Surg. 1996;223:384-394.
FULL TEXT
|
ISI
| PUBMED
13. Launois B, Reding R, Lebeau G, Buard JL. Surgery for hilar cholangiocarcinoma: French experience in a collective survey of 552 extrahepatic bile duct cancers. J Hepatobiliary Pancreat Surg. 2000;7:128-134.
FULL TEXT
| PUBMED
14. Tsao JI, Nimura Y, Kamiya J, et al. Management of hilar cholangiocarcinoma: comparison of an American and a Japanese experience. Ann Surg. 2000;232:166-174.
FULL TEXT
|
ISI
| PUBMED
15. Neuhaus P, Jonas S, Bechstein WO, et al. Extended resections for hilar cholangiocarcinoma. Ann Surg. 1999;230:808-818.
FULL TEXT
|
ISI
| PUBMED
16. Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982;5:649-655.
ISI
| PUBMED
17. Greene FL, ed. Extrahepatic bile ducts. In: American Joint Committee on Cancer: AJCC Cancer Staging Manual. 6th ed. New York, NY: Springer; 2002:145-150.
18. Bismuth H, Corlette MB. Intrahepatic cholangioenteric anastamosis in carcinoma of the hilus of the liver. Surg Gynecol Obstet. 1975;140:170-177.
ISI
| PUBMED
19. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc. 1958;53:457-481.
FULL TEXT
|
ISI
20. Peto R, Peto J. Asymptotically efficient rank invariant procedures. J R Stat Soc Ser A. 1972;135:185-207.
FULL TEXT
21. Cox DR. Regression models and life tables. J R Stat Soc Ser B. 1972;34:187-220.
22. Sauerbrei W, Schumacher M. A bootstrap resampling procedure for model building: application to the Cox regression model. Stat Med. 1992;11:2093-2109.
ISI
| PUBMED
23. Burke EC, Jarnagin WR, Hochwald SN, Pisters PW, Fong Y, Blumgart LH. Hilar cholangiocarcinoma: patterns of spread, the importance of hepatic resection for curative operation, and a presurgical clinical staging system. Ann Surg. 1998;228:385-394.
FULL TEXT
|
ISI
| PUBMED
24. Lee SG, Lee YJ, Park KM, Hwang S, Min PC. One hundred and eleven liver resections for hilar bile duct cancer. J Hepatobiliary Pancreat Surg. 2000;7:135-141.
FULL TEXT
| PUBMED
25. Nimura Y, Kamiya J, Kondo S, et al. Aggressive preoperative management and extended surgery for hilar cholangiocarcinoma: Nagoya experience. J Hepatobiliary Pancreat Surg. 2000;7:155-162.
26. Seyama Y, Kubota K, Sano K, et al. Long-term outcome of extended hemihepatectomy for hilar bile duct cancer with no mortality and high survival rate. Ann Surg. 2003;238:73-83.
FULL TEXT
|
ISI
| PUBMED
27. Kawasaki S, Makuuchi M, Miyagawa S, Kakazu T. Radical operation after portal embolization for tumor of hilar bile duct. J Am Coll Surg. 1994;178:480-486.
ISI
| PUBMED
28. Weber SM, DeMatteo RP, Fong Y, Blumgart LH, Jarnagin WR. Staging laparoscopy in patients with extrahepatic biliary carcinoma: analysis of 100 patients. Ann Surg. 2002;235:392-399.
FULL TEXT
|
ISI
| PUBMED
29. Kawasaki S, Imamura H, Kobayashi A, et al. Results of surgical resection for patients with hilar bile duct cancer: application of extended hepatectomy after biliary drainage and hemihepatic portal vein embolization. Ann Surg. 2003;238:84-92.
FULL TEXT
|
ISI
| PUBMED
30. Mizumoto R, Kawarada Y, Suzuki H. Surgical treatment of hilar carcinoma of the bile duct. Surg Gynecol Obstet. 1986;162:153-158.
ISI
| PUBMED
31. Nimura Y, Hayakawa N, Kamiya J, Kondo S, Shionoya S. Hepatic segmentectomy with caudate lobe resection for bile duct carcinoma of the hepatic hilus. World J Surg. 1990;14:535-543.
FULL TEXT
|
ISI
| PUBMED
32. Macdonald OK, Crane CH. Palliative and postoperative radiotherapy in biliary tract cancer. Surg Oncol Clin N Am. 2002;11:941-954.
FULL TEXT
| PUBMED
33. Wiedmann M, Caca K, Berr F, et al. Neoadjuvant photodynamic therapy as a new approach to treating hilar cholangiocarcinoma: a phase II pilot study. Cancer. 2003;97:2783-2790.
FULL TEXT
|
ISI
| PUBMED
34. Hassoun Z, Gores GJ, Rosen CB. Preliminary experience with liver transplantation in selected patients with unresectable hilar cholangiocarcinoma. Surg Oncol Clin N Am. 2002;11:909-921.
FULL TEXT
| PUBMED
|
