The Emergence of Liver Transplantation for Hilar Cholangiocarcinoma

THE EMERGENCE OF LIVER TRANSPLANTATION THE EMERGENCE OF LIVER TRANSPLANTATION FOR HILAR CHOLANGIOCARCINOMAFOR 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 The Emergence of Liver Transplantation for Hilar CholangiocarcinomaHilar Cholangiocarcinoma

• Cholangiocarcinoma

• Protocol

• Results

• Special problems

• Living donor transplantation

• MELD score adjustment

• Challenges and controversies

The Emergence of Liver Transplantation for The Emergence of Liver Transplantation for Hilar CholangiocarcinomaHilar Cholangiocarcinoma

A Success Story of Team Care and Combination TherapyA Success Story of Team Care and Combination TherapyGreg 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

CholangiocarcinomaCholangiocarcinoma

• 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

Hilar CholangiocarcinomaHilar 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

CholangiocarcinomaCholangiocarcinomaCincinnati 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

CholangiocarcinomaCholangiocarcinomaCincinnati Transplant Tumor Registry

207 patients, 1968 - 1997

0

20

40

60

80

100

0 1 2 3 4 5

Patient Survival, %

YearTransplantation 2000; 69:1633

CholangiocarcinomaCholangiocarcinomaSpanish 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 months13 intraabdominal

• 17 of 23 deaths (47%) due to recurrent disease


Incidental CholangiocarcinomaIncidental CholangiocarcinomaCanadian Transplant Experience

n=10

0

20

40

60

80

100

0 1 2 3

Patient

Disease-free

PercentSurvival

Year

Hepatology 2002; 36:228A

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Mayo Clinic Treatment ProtocolMayo Clinic Treatment ProtocolMayo Clinic Treatment ProtocolMayo Clinic Treatment Protocol

External beam radiation therapy

Brachytherapy

Protracted venous infusion of 5-FU

Abdominal exploration for staging

Liver transplantation

External beam radiation therapy

Brachytherapy

Protracted venous infusion of 5-FU

Abdominal exploration for staging

Liver transplantation

Hilar CholangiocarcinomaHilar CholangiocarcinomaMayo Clinic ApproachMayo Clinic Approach

1993 to Present1993 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 EligibilityPatient 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 CriteriaExclusion 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 TherapyRadiation 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

ChemotherapyChemotherapy

• 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 ToxicityRadiation and Chemotherapy Toxicity

• Nausea and vomiting

• Leukopenia

• Cholangitis

• Cholecystitis

• Gastroduodenal ulceration

• Gastroparesis

• Hepatic abscess

• Liver failure

Explanted Liver AfterNeoadjuvant Therapy

Surgical StagingSurgical 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 TransplantationLiver 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

Portal Vein

Portal Vein Division

Living Donor Transplant

Deceased Donor Transplant

Portal Vein Division

Cholangio-carcinoma

Cholangiocarcinoma

CP1084287-6CP1084287-6

Cholangiocarcinoma Treatment ProtocolCholangiocarcinoma Treatment ProtocolResults – August 2007Results – August 2007

Cholangiocarcinoma Treatment ProtocolCholangiocarcinoma Treatment ProtocolResults – August 2007Results – August 2007

147 patients147 patients147 patients147 patients 12 deaths, debilitation, or disease progression12 deaths, debilitation, or disease progression

1 transplant elsewhere 1 transplant elsewhere

1 deaths 1 deaths

121 staging 121 staging operationoperation

121 staging 121 staging operationoperation

25 (21%) positive25 (21%) positive

89 liver 89 liver transplantationtransplantation

89 liver 89 liver transplantationtransplantation

Irradiation + 5-FU

Irradiation + 5-FU

63 deceased donor63 deceased donor

25 living donor25 living donor

1 domino donor 1 domino donor

13 receiving neoadjuvant Rx 13 receiving neoadjuvant Rx

3 transplant elsewhere 3 transplant elsewhere

3 awaiting transplantation

Patient Survival After Start of TherapyPatient Survival After Start of Therapy1993 – 2007

n=147

0102030405060708090

100

0 1 2 3 4 5

%

Years after start of therapy

55 + 6%

Patient Survival After TransplantationPatient Survival After Transplantation1993 – 2007

n=89

0

10

20

30

40

50

60

70

80

90

100

0 1 2 3 4 5

%

Years after transplantation

73 + 7%

Disease-Free Survival After TransplantationDisease-Free Survival After Transplantation1993 – 2007

n=89

0102030405060708090

100

0 1 2 3 4 5

%


62 + 8%

Staging OperationStaging Operationn = 121n = 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

Cholangiocarcinoma Treatment ProtocolCholangiocarcinoma Treatment ProtocolOperative Staging ResultsLate versus Early Staging

LATE

Prior to September

2002

EARLY

After September

2002

Total

Staging 35 80 115

Findings precluding transplantation

11 13 24

Percent positive

31 16 21

Endoscopic UltrasoundEndoscopic 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

Cholangiocarcinoma Treatment ProtocolCholangiocarcinoma Treatment ProtocolResults – 89 Transplants

18 (20%) deaths:

• 5 surgical complications, 2 – 5 months

• 1 GVHD, 4 months

• 1 hematological disease, 31 months

• 11 recurrent CCA

Cholangiocarcinoma Treatment ProtocolCholangiocarcinoma Treatment ProtocolResults – 89 Transplants

Deaths due to surgical complications – 5:• Primary graft failure, HAT 1 5 months

HAT after retransplant, death during 2nd retransplant

• Unexplained, possible HAT1 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 TransplantationRecurrences After Liver Transplantationn=14n=14

Site Time StatusPerihepatic 7, 13, 17, 27 mo death at 9,18, 24, 43 mo

10 mo alive at 17moBiliary tube site 22 mo death at 24 moPeritoneum 22 mo death at 29 mo

24 mo alive at 29 moMediastinum 39 mo death at 64 moBone 7, 54 mo death at 10, 83 mo

7 mo alive at 28 moBrain, adrenal 46 mo death at 47 moRemnant CBD 64 mo death at 66 mo

Mean time to recurrence – 26 months

Recurrences After Liver TransplantationRecurrences After Liver Transplantationn=14n=14

Site Time StatusPerihepatic 7, 13, 17, 27 mo death at 9,18, 24, 43 mo

10 mo alive at 17moBiliary tube site 22 mo death at 24 moPeritoneum 22 mo death at 29 mo

24 mo alive at 29 moMediastinum 39 mo death at 64 moBone 7, 54 mo death at 10, 83 mo

7 mo alive at 28 moBrain, adrenal 46 mo death at 47 moRemnant CBD 64 mo death at 66 mo

5 of 14 (36%) recurrences distant metastases

Special ProblemsSpecial Problems

• Neoadjuvant therapy complications

• Hepatic decompensation

• Technical problems

• Late vascular problems


Medical and neoadjuvant therapy problems• DVT and PE

• Duodenal ulceration – perforation, bleeding

• Cholecystitis, gall bladder perforation


Hepatic decompensation

• Precluding staging

• After staging


Technical problems• Early hepatic artery thrombosis

• Caudate involvement

• Biliary Wall stents

• Adhesions

• Common bile duct involvement

Pancreatoduodenectomy and TransplantationPancreatoduodenectomy and Transplantationn = 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 InvolvementCommon Bile Duct InvolvementPancreatoduodenectomy


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 StenosisPortal Vein Stenosis

Portal Vein Angioplasty with StentPortal Vein Angioplasty with Stent

Living Donor Liver TransplantationLiving 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

CP1084287-9CP1084287-9

Living Donor Liver Transplantation for CCALiving Donor Liver Transplantation for CCA Deceased Versus Living Donor TransplantationLiving Donor Liver Transplantation for CCALiving Donor Liver Transplantation for CCA Deceased Versus Living Donor Transplantation

Survival(%)

Survival(%)

YearsYears

DDLTDDLT

LDLTLDLT

P=0.03P=0.03

0

20

40

60

80

100

0.0 0.5 1.0 1.5 2.0

93%

50%

Hassoun AASLD 2002

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Living Donor Liver TransplantationLiving Donor Liver TransplantationCholangiocarcinoma Versus Other Diagnoses

Living Donor Liver TransplantationLiving Donor Liver TransplantationCholangiocarcinoma Versus Other Diagnoses

Survival(%)

Survival(%)

YearsYears

OtherOther

CCACCA

P=0.006P=0.006

0

20

40

60

80

100

0.0 0.5 1.0 1.5 2.0

Hassoun AASLD 2002

Revisiting Living Donor Liver Revisiting Living Donor Liver Transplantation for CholangiocarcinomaTransplantation 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 DonorLiving Donor Versus Decease DonorLiver Transplantation for CCALiver Transplantation for CCA

20042004

N Hospitalization

Mean (range)

Vascular / Biliary Complications

Deceased Donor

8 16. 8 (7 – 70) 3 / 2

Living Donor

4 11.5 (9 – 15) 0 / 0

Taner ATC 2005

Patient Survival After TransplantationPatient Survival After Transplantation 2004 – 2006

0102030405060708090

100

0 1 2

Living Donor Transplant (12)

Deceased Donor Transplant (24)

%


79 + 15%

83 + 15%

Cholangiocarcinoma Treatment ProtocolCholangiocarcinoma Treatment ProtocolKey Questions

• Efficacy?

• Appropriate use of donor organs?

• Resection or transplantation?

• Prioritization for deceased donor liver allocation?

Cholangiocarcinoma Treatment ProtocolCholangiocarcinoma Treatment ProtocolKey Questions (update efficacy data)

• Efficacy?

–55% five-year survival overall

–73% five-year survival after transplantation

–62% five-year disease-free survival after transplantation





• Efficacy?




Patient Survival After TransplantationPatient Survival After TransplantationCCA Versus Other Diagnoses

0

10

20

30

40

50

60

70

80

90

100

0 1 2 3 4 5

CCA (28)

HCC (70)

HCV (147)

PSC (131)

%

Years after transplantationATC 2004


• Efficacy?




0

20

40

60

80

100

%

0 1 2 3 4 5

Time (years)

Transplantation (n=38)Resection (n=26)

Survival after OperationSurvival after Operation

92%

82% 82%

82%

48%

21%

ASA 2005

Survival after OperationSurvival after OperationPatients Patients WithoutWithout PSC 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

Survival from Start of TherapySurvival 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


• Efficacy?




MELD Score Adjustment for CCAMELD Score Adjustment for CCA Region 7 RRB Meeting

Chicago O’Hare September 2002

CP1084287-11CP1084287-11

Region 7 Score Adjustment for CCARegion 7 Score Adjustment for CCASeptember 2002 Agreement

March 2005 Score Adjustments

Region 7 Score Adjustment for CCARegion 7 Score Adjustment for CCASeptember 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

ScoreSep ‘02 Mar ‘05

Staging (immediate) 20 20

6 months 26 24

12 months 29 27

18 months 31 29

24 months 33 31

Staging to Transplant IntervalStaging to Transplant IntervalEnrollment after September 2002

52 of 81 registrations underwent transplantation

Staging to Transplantation

Interval

N Recurrences After

Transplantation

< 90 days 26 1 (4%)

> 90 days 26 6 (23%)

P < 0.05, Chi-square test

Challenges and ControversiesChallenges 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

SummarySummary

• 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

SummarySummary

• 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

ConclusionConclusion

Liver transplantation with neoadjuvant therapy has emerged as an effective treatment for patients with localized, regional lymph node negative, hilar cholangiocarcinoma

MELD Score Adjustment for CCAMELD Score Adjustment for CCARegion 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 donor transplantation

MELD Score Adjustment for CCAMELD Score Adjustment for CCARegion 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

CP1084287-11CP1084287-11

Region 7 Score Adjustment for CCARegion 7 Score Adjustment for CCARegistrations September 2002 – March 2007

N = 82


N = 82N %

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

N %

Neoadjuvant Rx 2 2

Protocol fall-out:


transplant ew 1 1

Staging 11 13


transplant ew 3 4


Transplantation: DD 36 44

LD 16 20

CP1084287-11CP1084287-11


N = 82


N = 82N %

Neoadjuvant Rx 2 2

Protocol fall-out:


transplant ew 1 1

Staging 11 13


transplant ew 3 4


Transplantation: DD 36 8 per year 44

LD 16 20

N %

Neoadjuvant Rx 2 2

Protocol fall-out:


transplant ew 1 1

Staging 11 13


transplant ew 3 4


Transplantation: DD 36 8 per year 44

LD 16 20

0

20

40

60

80

100

%

0 1 2 3 4 5Time (years)

All (n=38)Pathological confirmation (n=30)

Survival After Transplantation Survival After Transplantation Pathological ConfirmationPathological Confirmation

82%

80%

Transplantation versus Resection Study

Patient Survival After TransplantationPatient Survival After TransplantationExclusion of Patients Without Pathological Confirmation

1993 – 2006

0102030405060708090

100

0 1 2 3 4 5

ALL (65)

Biopsy/cytology confirmation (56)

%


76 + 8%

74 + 8%

Hilar CholangiocarcinomaHilar CholangiocarcinomaUniversity of Nebraska ProtocolUniversity 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

Hilar CholangiocarcinomaHilar CholangiocarcinomaUniversity 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


CP1084287-6CP1084287-6

University of Nebraska ResultsUniversity of Nebraska ResultsUniversity of Nebraska ResultsUniversity of Nebraska Results

17 patients17 patients17 patients17 patients

1 died from sepsis1 died from sepsis

1 tumor progression1 tumor progression

15 operation15 operation15 operation15 operation

Lymph node metastases - 3

Carcinomatosis - 1

Lymph node metastases - 3

Carcinomatosis - 1

11 transplantation11 transplantation11 transplantation11 transplantation

Irradiation + 5-FU

Irradiation + 5-FU

5 (45%) alive and disease-free at 2.8 - 14.5 years5 (45%) alive and disease-free at 2.8 - 14.5 years


Hilar CholangiocarcinomaHilar CholangiocarcinomaUniversity 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


Living Donor Liver TransplantationLiving Donor Liver TransplantationConfounding 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 StentCholangiocarcinoma with Wall Stent

Recipient Common Bile Duct Wall StentRecipient Common Bile Duct Wall Stent

Living Donor Artery StenosisLiving Donor Artery Stenosis

Hemobilia - LHA embolization, patent PVHemobilia - LHA embolization, patent PV

Portal Vein Obliteration, IVC Filter1.5 years after neoadjuvant therapy

Cholangiocarcinoma and PSCCholangiocarcinoma 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 GroupResection Groupn=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 GroupResection 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 months4 – hilus, 2 – liver, 1 – portal vein, 1 – peritoneum,

1 – umbilical trocar site

Survival after Resection Survival after Resection

0

20

40

60

80

100

%

0 1 2 3 4 5

Time (years)

All patients (n=26)R0, node-negative (n=15)Other (n=9)

Pathological Confirmation of Pathological Confirmation of Cholangiocarcinoma at Start of TherapyCholangiocarcinoma at Start of Therapy

n = 131Concerns

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 of Pathological Confirmation of Cholangiocarcinoma at Start of TherapyCholangiocarcinoma at Start of Therapy

n = 131Concerns

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

Pathological Confirmation of Pathological Confirmation of Cholangiocarcinoma and OutcomeCholangiocarcinoma and Outcome

n = 131

No Path Confirmation – 41

28 Transplants

7 recurrences

9 Fell Out

5 at staging

2 pre-staging

1 post-staging

Path Confirmation – 90

53 Transplants

7 recurrences

30 Fell Out

17 at staging

10 pre-staging

3 post-staging


n = 131


28 Transplants

13 (46%) – residual CCA

6 recurrences

15 (54%) – no residual CCA

1 recurrence

9 Fell Out

5 at staging

2 pre-staging

1 post-staging


53 Transplants

30 (57%) – residual CCA

6 recurrences

23 (43%) – no residual CCA

1 recurrence

30 Fell Out

17 at staging

10 pre-staging

3 post-staging


n = 131


13 – residual CCA

1 – no residual, recurrence

5 – positive at staging

19 – total: 46%


30 – residual CCA

1 – no residual, recurrence

17 – positive at staging

48 – total: 53%

Hilar CholangiocarcinomaHilar CholangiocarcinomaMayo Clinic ProtocolMayo Clinic ProtocolTimeline of ChangesTimeline 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

Explanted Liver AfterNeoadjuvant Therapy

Explanted Liver AfterNeoadjuvant Therapy: Duct Necrosis

Explanted LiverAfter NeoadjuvantTherapy: CCA and PSC

It may look like an apple

It may look like an apple

but it still tasteslike an orange

Cholangiocarcinoma Complicating PSCCholangiocarcinoma Complicating PSCUCLA - Liver Transplant Experience

0

20

40

60

80

100

0 1 2 3 4 5

Incidental - 10

Known - 4

None - 113

Patient Survival, %

Year


The Emergence of Liver Transplantation for Hilar Cholangiocarcinoma

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