The Emergence of Liver Transplantation For Hilar Cholangiocarcinoma

THE EMERGENCE OF LIVER TRANSPLANTATION
FOR HILAR CHOLANGIOCARCINOMA
Antalya, Turkey
September 3, 2007
Charles B. Rosen, MD
Surgical Director, Liver Transplantation
William J. von Liebig Transplant Center
Mayo Clinic Rochester
The Emergence of Liver Transplantation for
Hilar Cholangiocarcinoma
• Cholangiocarcinoma
• Protocol
• Results
• Special problems
• Living donor transplantation
• MELD score adjustment
• Challenges and controversies
The Emergence of Liver Transplantation for
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
Cemal Burcin Taner – Transplant Surgeon
David Rea – Surgery Resident
Henk-Jen Mantel – Medical Student
Liver Transplant Team
Medical and Radiation Oncology
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
Annals of Surgery 1991; 213:21
• 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
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
Cholangiocarcinoma
Cincinnati Transplant Tumor Registry
207 patients, 1968 - 1997
100
80
Patient 60
Survival, %
40
20
0
0 1 2 3 4 5
Year
Transplantation 2000;
69:1633
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
Incidental Cholangiocarcinoma
Canadian Transplant Experience
n=10
100
Patient
80 Disease-free
Percent 60
Survival
40
20
0
0 1 2 3
Year
Hepatology 2002; 36:228A

Mayo Clinic Treatment Protocol
External beam radiation therapy
Brachytherapy
Protracted venous infusion of 5-FU
Abdominal exploration for staging
Liver transplantation CP1084287-3

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
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
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
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
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
Radiation and Chemotherapy Toxicity
• Nausea and vomiting

• Leukopenia
• Cholangitis
• Cholecystitis
• Gastroduodenal ulceration
• Gastroparesis
• Hepatic abscess
• Liver failure
Explanted Liver After
Neoadjuvant Therapy
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
Liver Transplantation
• Avoid hilar dissection
• Arterial interposition graft with deceased
donor transplantation
• Low division of portal vein
• Portal vein interposition graft with living
• Caval replacement with caudate
involvement
• Frozen section of cut common bile duct
– pancreatoduodenectomy if positive
Portal Vein
Portal Vein Division
Living Donor Transplant
Deceased Donor Transplant

Portal Vein Division
Cholangio-
carcinoma
Cholangiocarcinoma
Cholangiocarcinoma Treatment Protocol
Results – August 2007
147 patients 12 deaths, debilitation, or
disease progression
Irradiation 1 transplant elsewhere
+ 5-FU
13 receiving neoadjuvant Rx
121 staging 25 (21%) positive
operation 3 awaiting transplantation
1 deaths
3 transplant elsewhere
63 deceased donor
89 liver
25 living donor
transplantation
1 domino donor
CP1084287-6
Patient Survival After Start of Therapy
1993 – 2007
n=147
100
90
80
70 55 + 6%
60
% 50
40
30
20
10
0
0 1 2 3 4 5
Years after start of therapy
Patient Survival After Transplantation
1993 – 2007
n=89
100
90 73 + 7%
80
70
60
% 50
40
30
20
10
0
0 1 2 3 4 5
Years after transplantation

Disease-Free Survival After Transplantation
1993 – 2007
n=89
100
90
80 62 + 8%
70
60
% 50
40
30
20
10
0
0 1 2 3 4 5
Staging Operation
n = 121
25 (21%) 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
Operative Staging Results
Late versus Early Staging
LATE EARLY Total
Prior to After
September September
2002 2002
Staging 35 80 115
Findings 11 13 24
precluding
transplantation
Percent positive 31 16 21
Endoscopic Ultrasound
• Routine use of EUS staging - with regional

lymph node aspiration - avoids neoadjuvant
therapy for many patients that would
otherwise fall-out at staging
• EUS guided aspiration of the primary tumor
causes seeding and should not be done
Results – 89 Transplants
18 (20%) deaths:
• 5 surgical complications, 2 – 5 months
• 1 GVHD, 4 months
• 1 hematological disease, 31 months
• 11 recurrent CCA
Results – 89 Transplants
Deaths due to surgical complications – 5:

• Primary graft failure, HAT 1 5 months
HAT after retransplant, death during 2nd retransplant
• Unexplained, possible HAT 1 3 months
• Complications of LDLT 3 2, 2, 4 months
Bile leak (Wall stent), sepsis
HAT, pseudoaneurysm, pancreatoduodenectomy
HAT, retransplantation, bile leak, sepsis
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
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
Special Problems
• Neoadjuvant therapy complications

• Hepatic decompensation
• Technical problems
• Late vascular problems
Special Problems
Medical and neoadjuvant therapy problems

• DVT and PE
• Duodenal ulceration – perforation, bleeding
• Cholecystitis, gall bladder perforation
Special Problems
Hepatic decompensation
• Precluding staging
• After staging
Special Problems
Technical problems
• Early hepatic artery thrombosis
• Caudate involvement
• Biliary Wall stents
• Adhesions
• Common bile duct involvement
Pancreatoduodenectomy and Transplantation
n = 10
• 9 of 56 (16%) PSC patients had positive CBD
margins
– 8 underwent pancreatoduodenectomy (4 DD, 2 LD, 1 AD)
» 6 alive and disease-free at 1 – 8 years
» 2 deaths within 3 months from HAT (DD) and
HAT/pseudoaneurysm (LD)
– 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 at 2 – 5 years
Common Bile Duct Involvement
Pancreatoduodenectomy
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
Liver Transplantation 2007 (in press)

Portal Vein Stenosis
Portal Vein Angioplasty with Stent
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
Living Donor Liver Transplantation for CCA
Deceased Versus Living Donor Transplantation
100 DDLT
93%
80
Survival 60 LDLT
50%
(%)
40
20 P=0.03
0
0.0 0.5 1.0 1.5 2.0
Hassoun AASLD 2002

Years
CP1084287-9
Cholangiocarcinoma Versus Other Diagnoses
100
Other
80
Survival 60 CCA
(%)
40
20 P=0.006
0
0.0 0.5 1.0 1.5 2.0
Hassoun AASLD 2002 Years
CP1084287-12
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
Living Donor Versus Decease Donor
Liver Transplantation for CCA
2004
N Hospitalization Vascular / Biliary
Mean (range) Complications
Deceased 8 16. 8 (7 – 70) 3/2

Donor
Living 4 11.5 (9 – 15) 0/0

Donor
Taner ATC 2005

2004 – 2006
100
90 83 + 15%
80
70 79 + 15%
60
% 50
40
30 Living Donor Transplant (12)
20
10 Deceased Donor Transplant (24)
0
0 1 2

Key Questions
• Efficacy?
• Appropriate use of donor organs?
• Resection or transplantation?
• Prioritization for deceased donor liver
allocation?
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
allocation?
Key Questions
• Efficacy?
allocation?
CCA Versus Other Diagnoses
100
90
80
70
60 CCA (28)
% 50
HCC (70)
40
30 HCV (147)
20 PSC (131)
10
0
0 1 2 3 4 5
ATC 2004 Years after transplantation

Key Questions
• Efficacy?
allocation?
Survival after Operation
100 92%
82% 82%
80
82%
60
%
40 48%
Transplantation (n=38)
Resection (n=26)
20
21%
0
0 1 2 3 4 5
ASA 2005 Time (years)

Survival after Operation
Patients Without PSC
100 94%
80
71% 71%
83%
60
% 42%
40
Transplantation (n=16)
20
Resection (n=24)
18%
0
0 1 2 3 4 5
ASA 2005 Time (years)
Survival from Start of Therapy
100
82%
80
79%
61%
58%
60
% 48%
40
Transplant protocol (n=71)
20 Resection (n=26)
21%
0
0 1 2 3 4 5
Time (years)
ASA 2005
Key Questions
• Efficacy?
allocation?
MELD Score Adjustment for CCA
Region 7 RRB Meeting
Chicago O’Hare September 2002
Region 7 Score Adjustment for CCA
September 2002 Agreement
March 2005 Score Adjustments
Score
Sep ‘02 Mar ‘05
Staging (immediate) 20 20
6 months 26 24
12 months 29 27
18 months 31 29
24 months 33 31 CP1084287-11
Staging to Transplant Interval
Enrollment after September 2002
52 of 81 registrations underwent transplantation
Staging to N Recurrences
Transplantation After
Interval Transplantation
< 90 days 26 1 (4%)
> 90 days 26 6 (23%)
P < 0.05, Chi-square test

Challenges and Controversies
• Deceased donor organ allocation
– Acceptance of efficacy
– Risks of disease progression after neoadjuvant therapy and
recurrence after transplantation with prolonged waiting time
– Prolongation of waiting time increases difficulty of transplantation
• Adoption of protocol by other centers
– Avoid compromising results with relaxation of criteria
• Screening for CCA in PSC patients
– Positive FISH and/or DIA studies with/without stricture
– Role of neoadjuvant therapy for very early stage disease
• Transplantation for potentially resectable CCA
• Pushing the envelope
– Patients with prior operations or biopsy
– Pancreatoduodenectomy
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
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
Conclusion
Liver transplantation with neoadjuvant therapy

has emerged as an effective treatment for
patients with localized, regional lymph node
negative, hilar cholangiocarcinoma
Region 7 RRB Meeting - September 2002
• Pre-MELD era
– Waiting time from registration
– Staging and status 2B appeal as time neared for
transplantation
• MELD February 2002: score adjustments to be
based on risk of death or progression of disease
beyond transplant criteria
What we knew:
• Excellent survival after neoadjuvant therapy,
operative staging, and transplantation
• 30% staged positive
• No relationship between staging-to-transplant interval
and recurrence – the interval was short by design
What we did not know:

• How many patients would stage positive at the outset
(no EUS up until that time)?
• How many patients that staged negative at the outset
would fall-out awaiting transplantation?
What we agreed to do in order to answer these

questions:
• Stage patients at completion of neoadjuvant
therapy and reassess at time of transplantation
• Adjust scores in parallel with current and future
stage I HCC score adjustments, but at twice the
interval, 6 mo instead of 3 mo
– Provide an opportunity for patients to receive a deceased donor liver
– Retain incentives for use of extended criteria donor livers and living
Region 7 RRB Meeting – March 2007
What we learned since September 2002:

• EUS achieves reasonably accurate initial staging
• Unfriendly operative field precludes accurate
reassessment at time of transplantation
• Prolongation of staging-to-transplant interval is
associated with higher rate of recurrent disease
What we proposed:
• Reverting to late operative staging – as the time nears
for transplantation
– Avoid transplanting patients destined to develop recurrence
• Decreasing the time interval for score increases to 3
months
– Avoid higher rate of recurrence observed with prolongation
of waiting time
– Score adjustments in accord with 3 month intervals
recommended for other conditions
What we proposed:
• Reverting to late operative staging – as the time nears
for transplantation AGREEMENT
– Avoid transplanting patients destined to develop recurrence
• Decreasing the time interval for score increases to 3
months DISAGREEMENT
– Avoid higher rate of recurrence observed with prolongation
of waiting time
– Score adjustments in accord with 3 month intervals
recommended for other conditions
Registrations September 2002 – March 2007
N = 82
N %
Neoadjuvant Rx 2 2
Protocol fall-out:
Pre-staging: death/too sick 4 5
transplant ew 1 1
Staging 11 13
Post-staging: death/progression 2 2
transplant ew 3 4
Awaiting transplantation 7 9
Transplantation: DD 36 44
LD 16 20
CP1084287-11
Registrations September 2002 – March 2007
N = 82
N %
Neoadjuvant Rx 2 2
Protocol fall-out:
Pre-staging: death/too sick 4 5
transplant ew 1 1
Staging 11 13
Post-staging: death/progression 2 2
transplant ew 3 4
Awaiting transplantation 7 9
Transplantation: DD 36 8 per year 44
LD 16 20
CP1084287-11
Survival After Transplantation
Pathological Confirmation
100
82%
80
80%
60
%
40 Transplantation versus Resection Study
All (n=38)
20 Pathological confirmation (n=30)
0
0 1 2 3 4 5
Time
(years)
Exclusion of Patients Without Pathological Confirmation
1993 – 2006
100
90
80 76 + 8%
70
74 + 8%
60
% 50
40
30 ALL (65)
20
Biopsy/cytology confirmation (56)
10
0
0 1 2 3 4 5
University of Nebraska Protocol
• Inclusion criteria
– maximum tumor dimension < 2cm
– absence of intra- and extra-hepatic metastases
– unresectable by conventional operation
• Cytological confirmation of diagnosis
– brush cytology 15
– FNA 2
• Neoadjuvant therapy
– Brachytherapy: 6000 cGy with Ir-192 wires
– IV 5-FU
• Liver transplantation
– regional lymphadenectomy prior to hepatectomy
– caval excision
American Journal of Transplantation 2002; 2:774

University of Nebraska Experience
Preoperative complications
• cholangitis: 9 of 17 patients (6 at diagnosis)
• sepsis and death: 1 patient
• biliary stent perforation: 4 patients
• biliary-portal fistula with hemobilia
• erosive gastritis: 1 patient

University of Nebraska Results
17 patients
1 died from sepsis
Irradiation
+ 5-FU 1 tumor progression
15 operation
Lymph node metastases - 3
Carcinomatosis - 1
5 (45%) alive and disease-free at

11 transplantation 2.8 - 14.5 years
American Journal of Transplantation 2002; 2:774 CP1084287-6

University of Nebraska Experience
Deaths after transplantation

• Infectious complications - 3 (2-12 weeks)
– Bacterial peritonitis, GI bleeding, sepsis
– Fungal pseudoaneurysm of HA/PV
– Pancreatoduodenectomy with anastomotic dehiscence and
splenic artery aneurysm
• Chronic rejection - 1 (1 year)
– Retransplantation, HAT, sepsis
• Tumor recurrence - 2 (4-5 months)
– Hepatic hilum with extension to duodenum: 537d
– VBDS, retransplantation at 1mo, duodenal recurrence: 310d

Confounding Issues
• Protocol enrollment “relaxation” - 3
– radical retropubic prostatectomy 2 years earlier -
retransplantation, death
– exploration for possible resection elsewhere, Wall stent -
death
– cholecystectomy, Roux Y choledochojejunostomy 10 years
earlier for PSC (no brachytherapy) recurrence (tube site),
death
• Pancreatoduodenectomy for unsuspected
distal common bile duct involvement - 1
– retransplantation for donor artery problem - alive and
disease-free at 22 months
Cholangiocarcinoma with Wall Stent
Recipient Common Bile Duct Wall Stent
Living Donor Artery Stenosis
Hemobilia - LHA embolization, patent PV
Portal Vein Obliteration, IVC Filter
1.5 years after neoadjuvant therapy
Cholangiocarcinoma and PSC
• CCA arises in 7-15% of patients with PSC
– Lindor et al USA 8%
– Aadland et al Sweden 8.9%
– Broome et al Sweden 13.8%
– Chapman et al UK 10.3%
• *Mayo Clinic D-penicillamine trial
– 5 of 70 (7%) of patients followed for 30 months in a
randomized medical therapy trial developed CCA
– CCA diagnosis established during 5 of 12 (42%)
autopsies
– No diagnoses of CCA in living patients
– CCA patients tended to be older and have had CUC
longer than patients with PSC alone
*Annals of Surgery 1991; 213:21
Resection Group
n=54
• 28 (52%) unresectable
– 11 (39%) vascular encasement
– 7 (25%) distant lymph node metastases
– 5 (18%) peritoneal metastases
– 4 (14%) intrahepatic metastases
– 1 (4%) inflammation and adhesions
• 26 (48%) resections
– 12 (46%) right hepatectomy
– 13 (50%) left hepatectomy
– 1 (4%) extended right hepatectomy
– Caudate resection 10 (38%)
• 23 (88%) R0 and 3 (12%) R1 (+ hepatic

duct margins)
Resection Group
26 resections
• 25 with invasive CCA, 1 with in-situ CCA and PSC
• 8 (31%) with regional lymph node involvement
• 15 (58%) with both R0 resection and absence of
regional lymph node involvement
• 3 (12%) postoperative deaths
dysrhythmia, bile leak, unknown cause at home
• 9 (35%) recurrences at mean of 21 months
4 – hilus, 2 – liver, 1 – portal vein, 1 – peritoneum,
1 – umbilical trocar site
Survival after Resection
100
80
60
%
40
All patients (n=26)

20
R0, node-negative (n=15)
Other (n=9)
0
0 1 2 3 4 5
Time (years)
Pathological Confirmation of
Cholangiocarcinoma at Start of Therapy
n = 131
Concerns
PSC patients did not have pathological confirmation
Separate CCA with PSC and de novo CCA patients
Review data on patients without pathological confirmation
Pathological confirmation of diagnosis prior to Rx

• 90 of 131 (69%) of all patients
• 29 of 49 (59%) de novo CCA patients
• 61 of 82 (74%) CCA with PSC patients
Cholangiocarcinoma at Start of Therapy
n = 131
Concerns
PSC patients did not have pathological confirmation
Separate CCA with PSC and de novo CCA patients
Review data on patients without pathological confirmation
Pathological confirmation of diagnosis prior to Rx

• 90 of 131 (69%) of all patients
• 29 of 49 (59%) de novo CCA patients
• 61 of 82 (74%)CCA with PSC patients
• Pathological confirmation more frequent with PSC
Cholangiocarcinoma and Outcome
n = 131
Path Confirmation – 90 No Path Confirmation – 41
53 Transplants 28 Transplants
7 recurrences 7 recurrences
30 Fell Out 9 Fell Out

17 at staging 5 at staging
10 pre-staging 2 pre-staging
3 post-staging 1 post-staging
n = 131
30 (57%) – residual CCA 13 (46%) – residual CCA
23 (43%) – no residual CCA 15 (54%) – no residual CCA
1 recurrence 1 recurrence
n = 131
30 (57%) – residual CCA 13 (46%) – residual CCA
23 (43%) – no residual CCA 15 (54%) – no residual CCA
1 recurrence 1 recurrence
n = 131
30 – residual CCA 13 – residual CCA

1 – no residual, recurrence 1 – no residual, recurrence
17 – positive at staging 5 – positive at staging
48 – total: 53% 19 – total: 46%
Mayo Clinic Protocol
Timeline of Changes
• 1993 – Discontinue liver biopsy at staging

Routine use of iliac arterial graft
• 1999 – Encouraging early results, increase in application
• 1999 – Pancreatoduodenectomy for CBD involvement
• 2000 – EUS guided regional lymph node aspiration
prior to neoadjuvant therapy
• 2001 – Poor results with 4 living donor transplantation
• 2002 – Region 7 agreement for score adjustment
• 2004 – Resume living donor transplantation
Neoadjuvant Therapy
Neoadjuvant Therapy:
Duct Necrosis
Explanted Liver
After Neoadjuvant
Therapy:
CCA and PSC
It may look like an apple
It may look like an apple
but it still tastes

like an orange
Cholangiocarcinoma Complicating PSC
UCLA - Liver Transplant Experience
100
80
Patient 60 Incidental - 10
Survival, % Known - 4
40 None - 113
20
0
0 1 2 3 4 5
Year

The Emergence of Liver Transplantation For Hilar Cholangiocarcinoma

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THE EMERGENCE OF LIVER TRANSPLANTATION

FOR HILAR CHOLANGIOCARCINOMA

• Second most common primary malignant liver

• Standard surgical resection has limited efficacy

Hepatology 2002; 36:228A

Protracted venous infusion of 5-FU

Abdominal exploration for staging

Liver transplantation CP1084287-3

• External beam radiotherapy

• 5-FU daily bolus for three consecutive days at

• Nausea and vomiting

Living Donor Transplant

Deceased Donor Transplant

Years after transplantation

• Routine use of EUS staging - with regional

Deaths due to surgical complications – 5:

• Neoadjuvant therapy complications

Medical and neoadjuvant therapy problems

Late vascular problems

Liver Transplantation 2007 (in press)

• Appears attractive for cholangiocarcinoma

Hassoun AASLD 2002

• Conservative inclusion criteria

Deceased 8 16. 8 (7 – 70) 3/2

Living 4 11.5 (9 – 15) 0/0

Taner ATC 2005

Years after transplantation

ATC 2004 Years after transplantation

ASA 2005 Time (years)

> 90 days 26 6 (23%)

P < 0.05, Chi-square test

Liver transplantation with neoadjuvant therapy

What we did not know:

What we agreed to do in order to answer these

What we learned since September 2002:

American Journal of Transplantation 2002; 2:774

American Journal of Transplantation 2002; 2:774

5 (45%) alive and disease-free at

American Journal of Transplantation 2002; 2:774 CP1084287-6

Deaths after transplantation

American Journal of Transplantation 2002; 2:774

• 23 (88%) R0 and 3 (12%) R1 (+ hepatic

All patients (n=26)

Pathological confirmation of diagnosis prior to Rx

Pathological confirmation of diagnosis prior to Rx

30 Fell Out 9 Fell Out

Path Confirmation – 90 No Path Confirmation – 41

30 – residual CCA 13 – residual CCA

• 1993 – Discontinue liver biopsy at staging

but it still tastes

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