liver transplantation how much have we evolved? benjamin philosophe, md, phd clinical chief of...

Liver TransplantationHow much have we evolved?

Benjamin Philosophe, MD, PhDClinical Chief of Transplantation

Johns Hopkins Medicine

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

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

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

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

Technique - “piggy back” vs. traditional bi-caval

Piggyback technique first described by Calne in 1968 popularized by Tzakis at the U. of Miami

Piggyback – Side to side caval anastomosis

Geographical division of the U.S. into “UNOS” Regions in the U.S.

Liver Allocation in the United States

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

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?

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

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

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.

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

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

Optimal time to Transplant


MELD

Death Rate/1000 PY


As of June 18, 2013, Anyone with a MELD of 35 or higher draws organs from the whole region

Allocation of Adult Deceased Donor Livers

Transplant Death Rate vs. MELD Score


Death Rate/1000 PY

163.3 127.4 164.7 174.1 178.4 176.9 195.9 245.5 264.6 Transplant

MELD

Optimal time to Transplant


MELD

Death Rate/1000 PY


Adult Living Donor Liver Transplantation

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

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

In adults, unlike kids, volume of the graft and its venous drainage is very important

Living Donor Liver Transplantation

Right lobe after reperfusion

Disease at time of Transplant - Incidence by YearA significant change in the landscape

Data from Organ Procurement and Transplantation Network (OPTN) - April, 2013

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

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

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

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%

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.

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?



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%

Disease at time of Transplant - Incidence by YearCholangiocarcinoma – Reemerging as an indication

Data from Organ Procurement and Transplantation Network (OPTN) - April, 2013

Impact of medical and surgical intervention on survival in patients with cholangiocarcinoma. Arrington AK, et al. 2013

Impact of medical and surgical intervention on survival in patients with CCA

Arrington AK, et al. 2013

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

A significant turning point …The MAYO Clinic Protocol

OLT for CholangiocarcinomaNeoadjuvant Therapy

Rea D.J. et al., 2005, 242(3)

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

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

Efficacy of Neoadjuvant Chemoradiation, Followed by Liver Transplantation, for Perihilar Cholangiocarcinoma at 12 US Centers. Murad et al., 2012. Gastroenterology; 143:88 – 98.

Recurrence-free survival for all transplanted patients (N = 214)


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).




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%

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?

liver transplantation how much have we evolved? benjamin philosophe, md, phd clinical chief of...

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