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LIVER TRANSPLANTATION FOR HILAR CHOLANGIOCARCINOMA
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Liver Transplantation for Hilar Cholangiocarcinoma
• Cholangiocarcinoma • Protocol • Results • Special problems • Living donor transplantation • MELD score adjustment • Challenges and controversies
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The Emergence of Liver Transplantation for Hilar Cholangiocarcinoma
A Success Story of Team Care and Combination Therapy Greg Gores – Transplant Hepatology Julie Heimbach – Transplant Surgeon Len Gunderson – Radiation Oncology Mike Haddock – Radiation Oncology
Steve Alberts – Medical Oncology David Nagorney – Hepatobiliary Surgeon
Jeff Steers – Transplant Surgeon Eduardo Ramos – Transplant Fellow Henk-Jen Mantel – Medical Student
Liver Transplant Team Medical and Radiation Oncology
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Cholangiocarcinoma
• Second most common primary malignant liver tumor
• Complication of primary sclerosing cholangitis • Associated with hepatolithiasis, choledochal
cysts, Caroli’s disease, biliary adenomata, parasite infections, and Thorotrast exposure
• Natural history of cholangiocarcinoma is poor, especially in the setting of primary sclerosing cholangitis
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Hilar Cholangiocarcinoma
• Standard surgical resection has limited efficacy – Few tumors are resectable – Long term survival <35% with complete resection
• Results with liver transplantation alone are poor • Lymph node metastases portend poor prognosis • Radiation with chemosensitization affords
palliation • University of Nebraska protocol with neoadjuvant
brachytherapy and liver transplantation
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Cholangiocarcinoma Cincinnati Transplant Tumor Registry
207 patients, 1968 - 1997
• PSC in addition to cholangiocarcinoma - 28% – No difference in survival
• Tumor recurrence - 51% – 84% within 2 years – 47% in allograft and 30% in lungs – Survival after recurrence less than 1 year
• No survival advantage for incidental tumors • No advantage of postoperative adjuvant therapy
Transplantation 2000; 69:1633
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Cholangiocarcinoma Cincinnati Transplant Tumor Registry
207 patients, 1968 - 1997
0
20
40
60
80
100
0 1 2 3 4 5
Patient Survival, %
Year Transplantation 2000; 69:1633
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Cholangiocarcinoma Spanish Liver Transplant Experience
36 patients, 1988 - 2001 • 36 hilar CCA transplants at 12 of 19 centers • 13 of 36 with hepatic lymph node involvement • 4 incidental tumors • Patient survival:
82% at one year 53% at two years 30% at three years
• 19 recurrences at mean of 21 months 13 intraabdominal
• 17 of 23 deaths (47%) due to recurrent disease Annals of Surgery 2004; 239:265
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Incidental Cholangiocarcinoma Canadian Transplant Experience
n=10
0
20
40
60
80
100
0 1 2 3
PatientDisease-free
Percent Survival
Year
Hepatology 2002; 36:228A
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Cholangiocarcinoma Complicating PSC UCLA - Liver Transplant Experience
0
20
40
60
80
100
0 1 2 3 4 5
Incidental - 10Known - 4None - 113
Patient Survival, %
Year Annals of Surgery 1997; 225:472
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CP1084287-3
Mayo Clinic Treatment Protocol External beam radiation therapy
Brachytherapy
Protracted venous infusion of 5-FU
Abdominal exploration for staging
Liver transplantation
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Hilar Cholangiocarcinoma Mayo Clinic Approach
1993 to Present
• Appear resectable – Resection with excision of extrahepatic bile
duct, regional lymphadenectomy, and right or left hepatectomy (+ caudate)
• Appear unresectable – Liver transplantation protocol
• Arising in setting of PSC – Liver transplantation protocol
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Patient Eligibility • Diagnosis of cholangiocarcinoma
– transcatheter biopsy or brush cytology – CA-19.9 >100 mg/ml with a malignant appearing
stricture on cholangiography – Biliary ploidy by FISH with a malignant appearing
stricture on cholangiography • Unresectable tumor above cystic duct
– Pancreatoduodenectomy for CBD tumors – Resectable CCA arising in PSC
• Absence of intra- and extrahepatic metastases • Candidate for liver transplantation
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Fluorescence in situ hybridization of biliary brushing. A representative fluorescence photomicrograph of biliary brushings from a patient with cholangiocarcinoma is shown here. Each colored spot represents one chromosome, therefore, 2 spots per color are indicative of the normal diploid state. In this example, >2 spots are seen for more than one color (indicating more than one chromosome pair is abnormal), leading to a diagnosis of polysomy.
FISH
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Exclusion Criteria
• Uncontrolled infection • Prior radiation or chemotherapy • Prior biliary resection or attempted resection • Transperitoneal biopsy (including EUS) • Intrahepatic metastases • Evidence of extrahepatic disease • History of other malignancy within 5 years
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Radiation Therapy
• External beam radiotherapy – inclusion of primary tumor and regional (porta hepatis,
celiac, and pancreatoduodenal) lymph nodes – window extended 3-5cm intrahepatically beyond ductal
involvement – 4000 to 4500 cGy
• Intraluminal brachytherapy – 2-3 weeks after completion of external beam therapy – Iridium inserted through endoscopic or percutaneous tubes – 2000 to 3000 cGy delivered to a 1cm radius
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Chemotherapy
• 5-FU daily bolus for three consecutive days at the beginning and end of external beam radiotherapy
• Protracted IV therapy begun with brachytherapy and continued until staging operation (daily for five weeks with one week off) and resumed afterward
• Oral capecitabine
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Radiation and Chemotherapy Toxicity
• Nausea and vomiting • Leukopenia • Cholangitis • Cholecystitis • Gastroduodenal ulceration • Gastroparesis • Hepatic abscess • Liver failure
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Surgical Staging
• Completion of brachytherapy – Initially as time nears for deceased donor transplantation – Since September 2002: immediately after brachytherapy for
those awaiting deceased donor transplantation – 2-7 days prior to living donor transplantation
• Thorough intraabdominal examination • Palpation of liver • Assess local extent of disease • Regional hepatic lymph node biopsies
– common hepatic artery lymph node – pericholedochal lymph node
• Hand-assisted laparoscopy for selected patients
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Liver Transplantation
• Avoid hilar dissection • Arterial interposition graft with deceased
donor transplantation • Low division of portal vein • Portal vein interposition graft with living
donor transplantation • Caval replacement with caudate involvement • Frozen section of cut common bile duct
– pancreatoduodenectomy if positive
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CP1084287-6
Cholangiocarcinoma Treatment Protocol Results – March 2007
131 patients 11 deaths, debilitation, or disease progression 1 transplant elsewhere
2 deaths
115 staging operation
24 (21%) positive
81 liver transplantation
Irradiation + 5-FU
60 deceased donor 20 living donor
1 domino donor
4 receiving neoadjuvant Rx
3 transplant elsewhere
5 awaiting transplantation
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Patient Survival After Start of Therapy 1993 – 2007
n=131
0102030405060708090100
0 1 2 3 4 5
%
Years after start of therapy
55 + 6%
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Patient Survival After Transplantation 1993 – 2007
n=81
0102030405060708090100
0 1 2 3 4 5
%
Years after transplantation
72 + 7%
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Disease-Free Survival After Transplantation 1993 – 2007
n=81
0102030405060708090100
0 1 2 3 4 5
%
Years after transplantation
62 + 8%
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Staging Operation n = 115
25 (22%) had findings precluding transplantation regional lymph node metastases 12 invasion of adjacent organs/tissues 4 intrahepatic metastases 3
peritoneal metastasis *6 (neuro-connective tissue)** (1) (gall bladder involvement)** (1)
*EUS transgastric aspiration site (primary tumor) **Missed at staging, found at LD and DD transplantation
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Cholangiocarcinoma Treatment Protocol Results – 81 Transplants
17 (22%) deaths: • 4 surgical complications, 2 – 5 months • 1 GVHD, 4 months • 1 hematological disease, 31 months • 11 recurrent CCA
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Cholangiocarcinoma Treatment Protocol Results – 81 Transplants
Deaths due to surgical complications – 4: • Primary graft failure, HAT 1 5 months
HAT after retransplant, death during 2nd retransplant
• Unexplained, possible HAT 1 3 months • Complications of LDLT 2 2, 4 months
Bile leak (Wall stent), sepsis HAT, retransplantation, bile leak, sepsis
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Recurrences After Liver Transplantation n=14
Site Time Status Perihepatic 7, 13, 17, 27 mo death at 9,18, 24, 43 mo
10 mo alive at 17mo Biliary tube site 22 mo death at 24 mo Peritoneum 22 mo death at 29 mo
24 mo alive at 29 mo Mediastinum 39 mo death at 64 mo Bone 7, 54 mo death at 10, 83 mo
7 mo alive at 28 mo Brain, adrenal 46 mo death at 47 mo Remnant CBD 64 mo death at 66 mo
Mean time to recurrence – 26 months
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Months after transplantation
0 12 24 36 48 60
Timing of CCA Recurrence After OLT
11/65 (17%) mean time = 29 months
median= 22 months site= metastatic 8, regional 3
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Special Problems
• Medical and neoadjuvant therapy problems • Hepatic decompensation • Technical problems • Late vascular problems
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Special Problems
Medical and neoadjuvant therapy problems • DVT and PE • Duodenal ulceration – perforation, bleeding • Cholecystitis, gall bladder perforation
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Special Problems
Hepatic decompensation • Precluding staging • After staging
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Recurrences After Liver Transplantation n=14
Site Time Status Perihepatic 7, 13, 17, 27 mo death at 9,18, 24, 43 mo
10 mo alive at 17mo Biliary tube site 22 mo death at 24 mo Peritoneum 22 mo death at 29 mo
24 mo alive at 29 mo Mediastinum 39 mo death at 64 mo Bone 7, 54 mo death at 10, 83 mo
7 mo alive at 28 mo Brain, adrenal 46 mo death at 47 mo Remnant CBD 64 mo death at 66 mo
5 of 14 (36%) recurrences distant metastases
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Special Problems
Technical problems • Early hepatic artery thrombosis • Caudate involvement • Biliary Wall stents • Adhesions • Common bile duct involvement
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Intrahepatic 6%
Perihilar 67%
Distal 27% ?
Distal Cholangiocarcinoma
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Pancreatoduodenectomy and Transplantation
n = 9 • 8 of 50 (16%) PSC patients had positive CBD
margins – 7 underwent pancreatoduodenectomy (4 DD, 2 LD, 1 AD)
» 6 alive and disease-free at 8 years to 7 days after transplantation
» 1 death at 3 months from presumed HAT – 1 adhesions precluded pancreatoduodenectomy
» alive with disease at 2 years • 2 PSC patients with prior biliary operations
underwent en bloc pancreatoduodenectomy – Alive and disease-free
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Common Bile Duct Involvement Pancreatoduodenectomy
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Special Problems
Late vascular problems • Overall incidence – 40% • Portal vein stenosis and thrombosis
– 22% with both living and deceased donor livers – Percutaneous angioplasty and stent insertion
• Hepatic artery stenosis and thrombosis – 21% with living donor grafts – Avoided by routine use of iliac graft with deceased
donor livers
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Living Donor Liver Transplantation
• Appears attractive for cholangiocarcinoma • Enables better timing of therapy
– neoadjuvant therapy – staging operation – transplantation
• Obviates problems with deceased donor organ availability and UNOS Regional Review Board appeals
– status 2B prior to change in allocation system – no standard score assignment with MELD/PELD system
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Revisiting Living Donor Liver Transplantation for Cholangiocarcinoma
• Conservative inclusion criteria • Strict exclusion criteria • Adjustment of neoadjuvant therapy • Timing of staging operation • Preferential avoidance of iliac
artery graft
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Patient Survival After Transplantation 2004 – 2006
0102030405060708090
100
0 1 2
Living Donor Transplant (12)
Deceased Donor Transplant (24)
%
Years after transplantation
79 + 15%
83 + 15%
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Cholangiocarcinoma Treatment Protocol Key Questions
• Efficacy? • Appropriate use of donor organs? • Resection or transplantation? • Prioritization for deceased donor liver
allocation?
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Cholangiocarcinoma Treatment Protocol Key Questions (update efficacy data)
• Efficacy? – 55% five-year survival overall – 73% five-year survival after transplantation – 62% five-year disease-free survival after
transplantation • Appropriate use of donor organs? • Resection or transplantation? • Prioritization for deceased donor liver
allocation?
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Cholangiocarcinoma Treatment Protocol Key Questions
• Efficacy? • Appropriate use of donor organs? • Resection or transplantation? • Prioritization for deceased donor liver
allocation?
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Patient Survival After Transplantation CCA Versus Other Diagnoses
0102030405060708090
100
0 1 2 3 4 5
CCA (28)
HCC (70)
HCV (147)
PSC (131)
%
Years after transplantation ATC 2004
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Cholangiocarcinoma Treatment Protocol Key Questions
• Efficacy? • Appropriate use of donor organs? • Resection or transplantation? • Prioritization for deceased donor liver
allocation?
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0
20
40
60
80
100
%
0 1 2 3 4 5
Time (years)
Transplantation (n=38) Resection (n=26)
Survival after Operation 92%
82% 82%
82%
48%
21%
ASA 2005
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Survival after Operation Patients Without PSC
0
20
40
60
80
100
%
0 1 2 3 4 5 Time (years)
Transplantation (n=16) Resection (n=24)
94%
71% 71% 83%
42%
18%
ASA 2005
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Survival from Start of Therapy
%
0
20
40
60
80
100
0 1 2 3 4 5 Time (years)
Transplant protocol (n=71) Resection (n=26)
79% 61% 58%
82%
48%
21%
ASA 2005
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Cholangiocarcinoma Treatment Protocol Key Questions
• Efficacy? • Appropriate use of donor organs? • Resection or transplantation? • Prioritization for deceased donor liver
allocation?
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Summary
• Combined chemoradiation therapy and liver transplantation achieves excellent results for highly selected patients with early stage disease - 73% patient survival at 5 years
• Operative staging is essential - findings preclude transplantation for ~20% of patients
• Morbidity is significant but not prohibitive • Living donor transplantation is an attractive
option for patients with cholangiocarcinoma
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Summary
• Patient survival after liver transplantation with this protocol exceed results reported with resection for hilar CCA
• Results compare favorably with survival after liver transplantation for chronic liver disease and hepatocellular carcinoma
• Results warrant due consideration for deceased donor liver allocation by UNOS Regional Review Boards
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Conclusion
Liver transplantation with neoadjuvant therapy has emerged as an effective treatment for patients with localized, regional lymph node negative, hilar cholangiocarcinoma
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