liver transplantation how much have we evolved? benjamin philosophe, md, phd clinical chief of...
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Liver TransplantationHow much have we evolved?
Benjamin Philosophe, MD, PhDClinical Chief of Transplantation
Johns Hopkins Medicine
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Immunosuppression and Outcome
Survival in the history of Liver Transplantation
1963 – First human liver transplant
1967 – First 1 year liver transplant survival
1970’s – 1 year survival 25% with Imuran and Prednisone1981 – Cyclosporine A introduced (NEJM)
1989 – Starzl introduces FK-506 (Lancet)
1994 - FK-506 FDA approved
One y
ear
pati
ent
surv
ival
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Liver Transplantation Today
What has changed?Technique
• Less venovenous bypass• More “piggyback”
Complexity of Transplant• Adult to Adult Living donor
Organ Allocation• MELD score replacing Child’s classification
Patient Selection• HIV• Advanced HCC• Cholangiocarcinoma
Diseases• More Hepatitis C compared to 20 years ago• More HCC• More NASH• Less Hepatitis B
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Traditional hepatectomy first described by Starzl involves resection of a segment of IVC in both the recipient and donor
Significant hemodynamic instability due to decrease venous return. 10% intraoperative mortality reported in 1984.B. Shaw Jr, et al. Venous bypass in clinical liver transplantationAnn Surg, 200 (1984), pp. 524–534
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Venovenous Bypass in Adult OLT
Chari RS et al., JACS 1998, 186(6): 683-690.
82% of NA centers were using during hepatectomy and anhepatic phase95% of NA centers were using only during anhepatic phase
Complication rate 10-30 %•Lymphoceles•Hematomas•Major vascular injury•Air embolism•Death
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Technique - “piggy back” vs. traditional bi-caval
Piggyback technique first described by Calne in 1968 popularized by Tzakis at the U. of Miami
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Piggyback – Side to side caval anastomosis
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Geographical division of the U.S. into “UNOS” Regions in the U.S.
Liver Allocation in the United States
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Donor Service Area (DSA) arbitrarily defined as an area served byOrgan Procurement Organization (OPO)
State(s) Donor Service Area (DSA),Organ Procurement Organization
# Liver Donors 2012
Liver Transplant Centers(Adult)
DC, Northern Virginia Washington Regional Transplant Community
109 • Georgetown
Maryland Living Legacy Foundation 122 • Johns Hopkins• U. Of Maryland
New Jersey New Jersey Organ and Tissue Sharing Network
89 • Our Lady of Lourdes• University Hospital
Pennsylvania, Delaware Gift of Life (PA and DE) 361 • Albert Einstein• Geisinger• Penn State/Hershey• Thomas Jefferson• Temple• U. of Pennsylvania
Western PA, West Virginia Center for Organ Recovery 175 • Allegheny General• U. of Pittsburgh• VA of Pittsburgh
Region 2
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Old System (PRE-MELD)Childs-Pugh Scoring - Waiting time emphasized
Acute Liver FailureSTATUS 1 - Fulminant hepatic Failure
– Primary non-function of transplant, < 7 days– Hepatic artery thrombosis, < 7 days
Chronic Liver Disease
STATUS 2A - Patients have > 10 POINTS– Patient in critical care unit– Life expectancy less than 7 days
STATUS 2B - Patients having > 10 POINTS– Stage I or II HCC
• One tumor < 5cm
• 2 or 3 tumors, none >3cm
STATUS 3 - Patients requiring ongoing medical therapy and
having > 7 POINTS
HOW ARE PATIENTS PRIORITIZED?
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Allocation within a DSA Prioritization by MELD score
• Model for End-Stage Liver Disease
• Developed at the Mayo Clinic (MN)
• Score is an estimate of the patient’s risk of mortality while on the transplant list
• Uses objective criteria to determine severity of illness and significantly reduces the influence of waiting time
• Based on model to predict short term prognosis of patients with cirrhosis undergoing TIPS procedure (also from the Mayo Clinic)
– Malinchoc M. et al., Hepatology 2000; 31: 864-871
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MELD Scoring SystemUNOS Modifications
Prognostic Factor Regression Coefficient P ValueSerum Creatinine(Loge value)
0.957 <0.01
Serum bilirubin(Loge value)
0.378 <0.01
INR(Loge value)
1.12 <0.01
[ 0.957 x Loge(Cr) + 0.378 x Loge(bili) + 1.120 x Loge (INR) + 0.643 ] x 10•Maximum Creatinine is 4 mg/dl•Patients on dialysis – Creatinine = 4mg/dl•Lowest score is 6•Maximum score is 40
Patrick Kamath et al. Hepatology 2001; 33(2): 464-470
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MELD Mortality EquivalentsMELD 3-Month
Mortality
7 1%
20 8%
22 10%
24 15%
26 20%
29 30%
31 40%
33 50%
35 60%
37 70%
38 80%
40 90%
The implementation of MELD as an organ allocation system has reduced mortality on the waiting list without affecting post-transplantation survival compared to the pre-MELD era.
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Transplant Benefit vs. MELD Score
44.8 52.5 146.4 271.9 514.9 840.7 1,663.8 4,634.1 13,152.7 Waitlist163.3 127.4 164.7 174.1 178.4 176.9 195.9 245.5 264.6 Transplant
MELD
Death Rate/1000 PY
Merion et al., 2005. Survival Benefit of Liver Transplantation. AJT; 5(2):307
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Yearly Deaths on Waitlist compared to Transplants
As of September 13, 2013 - 15,837 on the list for a liver transplant in the US
Data from Organ Procurement and Transplantation Network (OPTN) - September, 2013
6,256
2,931
194
11,092
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Optimal time to Transplant
44.8 52.5 146.4 271.9 514.9 840.7 1,663.8 4,634.1 13,152.7 Waitlist163.3 127.4 164.7 174.1 178.4 176.9 195.9 245.5 264.6 Transplant
MELD
Death Rate/1000 PY
Merion et al., 2005. Survival Benefit of Liver Transplantation. AJT; 5(2):307
As of June 18, 2013, Anyone with a MELD of 35 or higher draws organs from the whole region
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Allocation of Adult Deceased Donor Livers
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Transplant Death Rate vs. MELD Score
Merion et al., 2005. Survival Benefit of Liver Transplantation. AJT; 5(2):307
Death Rate/1000 PY
163.3 127.4 164.7 174.1 178.4 176.9 195.9 245.5 264.6 Transplant
MELD
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Optimal time to Transplant
44.8 52.5 146.4 271.9 514.9 840.7 1,663.8 4,634.1 13,152.7 Waitlist163.3 127.4 164.7 174.1 178.4 176.9 195.9 245.5 264.6 Transplant
MELD
Death Rate/1000 PY
Merion et al., 2005. Survival Benefit of Liver Transplantation. AJT; 5(2):307
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Adult Living Donor Liver Transplantation
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Yearly Deaths on Waitlist compared to Transplants
As of September 13, 2013 - 15,837 on the list for a liver transplant in the US
Data from Organ Procurement and Transplantation Network (OPTN) - September, 2013
6,256
2,931
194
11,092
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LIVING DONOR
• Around 200 performed in US annually
• Donor morbidity - 10-15%
• donor death - <0.5%
• Modifications in surgical techniques have reduced donor and recipient complications
• Some centers - LDLT comprises >40% of cases
• Recipient survival after living donor liver transplant equals survival of deceased donor liver transplant
Adult Liver Transplantation
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In adults, unlike kids, volume of the graft and its venous drainage is very important
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Living Donor Liver Transplantation
Right lobe after reperfusion
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Disease at time of Transplant - Incidence by YearA significant change in the landscape
Data from Organ Procurement and Transplantation Network (OPTN) - April, 2013
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Liver Transplantation for HCC
Ideal Therapy for cirrhotic patients with HCC
• Radical resection
• No residual cirrhotic liver
• Replaces poorly functioning hepatic parenchyma with normal liver
• Improved disease-free survival over resection
• Improved overall survival over resection
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Liver Transplantation for the Treatment of Small Hepatocellular Carcinomas in Patients with Cirrhosis
Vincenzo Mazzaferro, M.D., Enrico Regalia, M.D., Roberto Doci, M.D., Salvatore Andreola, M.D., Andrea Pulvirenti, M.D., Federico Bozzetti, M.D., Fabrizio Montalto, M.D., Mario Ammatuna, M.D., Alberto Morabito,
Ph.D., and Leandro Gennari, M.D., Ph.D.
The “Milan” group
March 14, 1996
• Small HCC criteria T1 and T2 and some T3
- Single lesion < 5 cm
- 2-3 lesions, none greater than 3 cm
- Bilobar ok
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Correlation of Post-Transplantation Pathological Confirmation of Early-Stage Hepatocellular Carcinoma with Overall Survival among 48 Patients with Cirrhosis
Mazzaferro, V. et al. N Engl J Med 1996;334:693-700
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Allocation of Livers using MELDMortality Equivalents
MELD 3-Month Mortality
7 1%
20 8%
“Milan” HCC 22 10%
24 15%
26 20%
29 30%
31 40%
33 50%
35 60%
37 70%
38 80%
41 90%
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Surgical Management of Early-Stage Hepatocellular Carcinoma: Resection or Transplantation?
Overall Survival (%) 1 yr 3 yrs 5 yrs P value
Transplant 91 79 66 <.001
Resection 93 71 46
DF Survival (%) 1 yr 3 yrs 5 yrs P value
Transplant 96 89 82 <.001
Resection 88 62 40
Bellavance et al., J Gastrointest Surg. 2008; (10):1699-708.
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Proposed expanded criteria based on tumor size & number in deceased donor liver transplantation
Author (year) Proposed expanced criteria
Radiology/ pathology
5 year patient survival
Milan
5 year patient survival
EC
Yao (2001), UCSF 1 nodule < 6.5 cm, or 2-3 nodules < 4.5 cm and total tumor diameter < 8 cm
Pathology 72% 73%
Yao (2007), UCSF Same as above Radiology 80% 82%
Herrero (2001), Pamplona, Spain
1 nodule < 6cm, or 2-3 nodules each < 5 cm
Radiology NA Entire group, 79%
Roayaie (2002), Mt.Sinai, NY 1 or more nodules 5 to 7 cm
Radiology NA 55%1
Kneteman (2004), Edmonton, Canada
1 nodule < 7.5 cm
any number < 5 cm
Radiology 87% (4 year) 73% (4 year)
Onaca (2007), International Tumor Registry
1 nodule < 6 cm 2-4 nodules each < 5 cm
Pathology 62%1 54.3%1
UCSF = University of California, San Francisco; EC = expanded criteria •1 Recurrence-free survival
Is the Milan criteria too restrictive?
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Allocation of Livers using MELDMortality Equivalents
MELD 3-Month Mortality
7 1%
20 8%
“UCSF” HCC 22 10%
24 15%
26 20%
29 30%
31 40%
33 50%
35 60%
37 70%
38 80%
41 90%
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Disease at time of Transplant - Incidence by YearCholangiocarcinoma – Reemerging as an indication
Data from Organ Procurement and Transplantation Network (OPTN) - April, 2013
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Impact of medical and surgical intervention on survival in patients with cholangiocarcinoma. Arrington AK, et al. 2013
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Impact of medical and surgical intervention on survival in patients with CCA
Arrington AK, et al. 2013
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Impact of medical and surgical intervention on survival in patients with CCA
Arrington AK, et al. 2013
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Author Year LTx (n) Neo-/adj Rx (n) SurvivalAlessiani 1995 12 25% 4 years
Cherqui 1995 2 (2) RTx 23 months (med.)
Anthuber 1996 10 25 months (med.)
Pichlmayr 1996 25 15.5 months (med.) 21.4% 3 years
Beckurts 1997 5 (5) IORT 12 months (med.)
Iwatsuki 1998 38 (18) RTx +/- 5-FU 12.7 cum 26% 5 years
Jonas 1998 14 30% 4 years
De Vreede 2000 11 (11) RTx +/- 5-FU 44 months (med.)
Sudan 2002 11 (11) BBT + 5-FU 17 months (med.)
Robles 2004 36 55 months (cum.) 53% 3 years
Heimbach 2004 28 RTx +/- 5-FU+ 82% 5 years
BBT + 5-FU/Gemcitabine
Rea 2005 38 RTx +/- 5-FU+ 87% 5 years
BBT + 5-FU/Gemcitabine
OLT for Cholangiocarcinomainitial experience was poor
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Author Year LTx (n) Neo-/adj Rx (n) SurvivalAlessiani 1995 12 25% 4 years
Cherqui 1995 2 (2) RTx 23 months (med.)
Anthuber 1996 10 25 months (med.)
Pichlmayr 1996 25 15.5 months (med.) 21.4% 3 years
Beckurts 1997 5 (5) IORT 12 months (med.)
Iwatsuki 1998 38 (18) RTx +/- 5-FU 12.7 cum 26% 5 years
Jonas 1998 14 30% 4 years
De Vreede 2000 11 (11) RTx +/- 5-FU 44 months (med.)
Sudan 2002 11 (11) BBT + 5-FU 17 months (med.)
Robles 2004 36 55 months (cum.) 53% 3 years
Heimbach 2004 28 RTx +/- 5-FU+ 82% 5 years
BBT + 5-FU/Gemcitabine
Rea 2005 38 RTx +/- 5-FU+ 87% 5 years
BBT + 5-FU/Gemcitabine
OLT for Cholangiocarcinomainitial experience was poor
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A significant turning point …The MAYO Clinic Protocol
OLT for CholangiocarcinomaNeoadjuvant Therapy
Rea D.J. et al., 2005, 242(3)
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Ext Beam Radiation
Chemo (radiosensitization)
OLT
Staging Laparotomy
Chemotherapy
Trans-luminal Boost
Target dose 4500 cGy30 fractions
Over 3 weeks period Iv 5-FU
100 mg/m2 daily bolus1st3 days of EBR
2-3 weeks
Transcatheter iridium seedsTarget dose 2000-3000 cGy
Capecitabine 2gm/m2/dayIn 2 divided doses
2/3 weeks until OLT 2-3 weeks
Bx. any large LN or noduleExamine tumorRoutine Bx. regional LN
-ve
Low dissection: CBD, HA, PVFrozen of CBD if +ve WhippleInterposition graft to Aorta
Standard: Tac, MMF, PredTac only by 4 monthAnnual CT chest, abd, CA 19-9
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1 yr – 92%3 yr – 82%5 yr – 82%
1 yr – 82%3 yr – 48%5 yr – 21%
Rea D.J. et al., 2005, 242(3)
Patient survival from Operation
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Efficacy of Neoadjuvant Chemoradiation, Followed by Liver Transplantation, for Perihilar Cholangiocarcinoma at 12 US Centers. Murad et al., 2012. Gastroenterology; 143:88 – 98.
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Recurrence-free survival for all transplanted patients (N = 214)
Efficacy of Neoadjuvant Chemoradiation, Followed by Liver Transplantation, for Perihilar Cholangiocarcinoma at 12 US Centers. Murad et al., 2012. Gastroenterology; 143:88 – 98.
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Kaplan Meier recurrence-free survival curves for(A)patients who are within UNOS/OPTN criteria for standard MELD exception (N = 166) vs those who are not (N = 48)(B) B) patients with a mass larger than 3 cm (N = 23) vs 3 cm or smaller (N = 191).
Efficacy of Neoadjuvant Chemoradiation, Followed by Liver Transplantation, for Perihilar Cholangiocarcinoma at 12 US Centers. Murad et al., 2012. Gastroenterology; 143:88 – 98.
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Allocation of Livers using MELDMortality Equivalents
MELD 3-Month Mortality
7 1%
20 8%
HCC and CCA 22 10%
24 15%
26 20%
29 30%
31 40%
33 50%
35 60%
37 70%
38 80%
41 90%
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Summary• Advances early on has been driven by Immunosuppression, but
outcomes have not changed significantly in the past 20 years.
• MELD has changed liver allocation by de-emphasizing waiting time
and decreasing mortality on the waiting list.
• Medical diagnoses have changed over time. The rising stars are
NASH, HCC and Cholangiocarcinoma. Hepatitis C remains the most
prominent diagnoses in most of the country but appears to be on the
decline.
• Liver transplantation should be the treatment of choice for HCC in
cirrhotics within UCSF criteria.
• Liver transplantation should be the treatment of choice for
unresectable hilar CCA less than 3 cm in size.
• Should we evaluate hilar CCA first for transplant?