THE EMERGENCE OF LIVER TRANSPLANTATION THE EMERGENCE OF LIVER TRANSPLANTATION FOR HILAR CHOLANGIOCARCINOMA 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
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The Emergence of Liver Transplantation for Hilar Cholangiocarcinoma
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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
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
%
Years after transplantation
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
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
Special ProblemsSpecial Problems
Medical and neoadjuvant therapy problems• DVT and PE
• Duodenal ulceration – perforation, bleeding
• Cholecystitis, gall bladder perforation
Special ProblemsSpecial Problems
Hepatic decompensation
• Precluding staging
• After staging
Special ProblemsSpecial Problems
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
Special ProblemsSpecial 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 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
CP1084287-12CP1084287-12
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
• Prioritization for deceased donor liver allocation?
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
MELD Score Adjustment for CCAMELD Score Adjustment for CCARegion 7 RRB Meeting - September 2002
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
MELD Score Adjustment for CCAMELD Score Adjustment for CCARegion 7 RRB Meeting - September 2002
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?
MELD Score Adjustment for CCAMELD Score Adjustment for CCARegion 7 RRB Meeting - September 2002
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
MELD Score Adjustment for CCAMELD Score Adjustment for CCARegion 7 RRB Meeting – March 2007
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
MELD Score Adjustment for CCAMELD Score Adjustment for CCARegion 7 RRB Meeting – March 2007
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
Region 7 Score Adjustment for CCARegion 7 Score Adjustment for CCARegistrations September 2002 – March 2007
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:
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
CP1084287-11CP1084287-11
Region 7 Score Adjustment for CCARegion 7 Score Adjustment for CCARegistrations September 2002 – March 2007
N = 82
Region 7 Score Adjustment for CCARegion 7 Score Adjustment for CCARegistrations September 2002 – March 2007
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 8 per year 44
LD 16 20
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
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)
%
Years after transplantation
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
American Journal of Transplantation 2002; 2:774
CP1084287-6CP1084287-6
University of Nebraska ResultsUniversity of Nebraska ResultsUniversity of Nebraska ResultsUniversity of Nebraska Results