Liver transplant in hepatocellular carcinoma
(Topic presentation By Dr Sidra Zahoor - Continuing Medical Education - CME )
Outline
Indications
Milan Criteria
Expanded Milan Criteria (UCSF)
Upto 7 Criteria
MELD Scoring and T staging
Criteria for down staging
LT versus LDT
Pre transplant Evaluation
Procedure
Follow up
Indications: The Milan Criteria
1996, Italy, 48 patients, Mazzafero et al
Single lesion less than 5 cm
Less than 3 lesions none exceeding 3cm
No extrahepatic involvement
No vascular invasion
overall and recurrence-free survivals were 85% and 92%
overall recurrence rate was 8% at 4 years’ follow-up
UCSF-Expanded Milan Criteria
2001
Solitary tumor < 6.5 cm,
or < 3 nodules with the largest lesion < 4.5 cm
and total tumor diameter < 8 cm
Schwartz, Liver Transplantation for Hepatocellular Carcinoma, Gastroenterology. 2004: 127 S268-276.
Vascular invasion
Mc Gill Protocol
Tumors exceeding Milan criteria
Receive 3 TACE treatments at 6 week intervals
Lipiodol,carboplatinum, gelfoam
If patients respond (AFP decreases or tumors shrink, then go on to LT, otherwise continue care)
Upto 7 criteria
HCC with 7 as the sum of the largest tumor (cm) and the number of tumors
Downstaging
LT versus LDT
LDT includes
TACE
RFA
PEI
The published observational studies to date suggest survival following OLT is at least as good as following resection in patients with adequate hepatic reserve.
Liver resection can leave residual liver which is of insufficient size to provide adequate function and as stated before, has the possibility of developing further lesions.
In patients with well-compensated cirrhosis (Child Pugh A) and HCC, the decision whether to resect or transplant remains controversial. However, in the current realm of organ shortage and long waiting times, the decision to resect in this group appears attractive.
If tumor recurrence were to recur than salvage transplantation can be performed.
An observational series has shown primary OLT to have lower operative mortality, recurrence rates and survival rates
Requirements for listing
UNOS provides a set of specific requirements for listing patients with HCC:
(1)Rough evaluation of the number and size of tumors and to rule out extra-hepatic spread by ultrasound, computed tomography (CT) or magnetic resonance imaging (MRI) plus CT of the chest;
(2) Prelisting biopsy is not mandatory, however patients must have one of the following:
(a) a biopsy confirming HCC;
(b) a vascular blush corresponding to the area of suspected HCC;
(c) an α fetoprotein (AFP) > 200 mg/mL;
(d) an arteriogram confirming a tumor;
(e) a history of local ablative therapy(TACE, RFA, PEI);
(3) Patients with chronic liver disease and a rising AFP > 500 mg/dL can also be listed even in the absence of discrete tumor on imaging studies;
(4) The patient must not be a resection candidate;
(5) Reimaging by CT or MRI every 3 mo is required to ensure continued eligibility for OLT.
Bridging therapy
The “dropout” due to tumor progression whilst waiting for OLT is reported to be at least 20%
This problem has furthered the use of local-regional adjuvant therapy (LDT) whilst awaiting transplantation such as TACE, RFA, and PEI.
The ultimate aim of LDT is to provide complete tumor necrosis in an attempt to halt tumor progression.
Analyses of explant specimens subjected to RFA and TACE have shown complete tumor necrosis rates of 47%-66% and 16%-27%, respectively
A retrospective study looking at tumor necrosis in 61 patients did not find any particular modality of LDT to be superior.
Prognostic Factors
Conforming to the “Milan criteria”, in terms of tumor size and tumor burden, gives rise to 3-4-year recurrence free survival rates of up to 92%
Multivariate analysis has shown these to be the only independent variables predicting patient survival and tumor recurrence. Other biological factors such as tumor grading, microvascular invasion and microsatellites appear to play a role, but within the constraints of the size and number burden.
The histological grade of the tumor can be assessed by lesional biopsy and several authors have recommended this approach. Lesional biopsy does however carry the risk of tumor seeding which has been estimated at approximately 2%
Furthermore, significant histological heterogeneity has been described in large tumors, which limits the utility of needle biopsy
Live donor LT
Living donor liver transplantation (LDLT) has evolved over the past decade, mainly in response to the scarcity of donor livers. Deceased liver donation is particularly scarce in Asia, where organ donation rates are less than 5 donors per million population compared to 10-35 per million in Western countries.
LDLT, in particular right liver transplantation, has dramatically increased the number of potential donors. This can eliminate the problem of long waiting times and ‘dropout’ whilst waiting for an organ because of disease progression.
Furthermore, as there is no direct ‘competition’ from other potential transplant recipients the restrictive criteria on tumor burden can be relaxed somewhat.
Survival rates-same as OLT
Recurrence rates-higher
No consensus guidelines for indications
LDLT carries a risk to the donor during hepatectomy with morbidity and mortality rates of 14%-21% and 0.25%-1%, respectively
Using a scoring system including the measurement of “protein induced by vitamin K absence or antagonist-Ⅱ” (PIVKA-Ⅱ), a Japanese group have achieved a 5-year recurrence rate of only 4.9%. PIVKA-Ⅱ, also known as des-carboxyprothrombin, is an abnormal prothrombin protein found in the serum of patients with HCC and in patients with vitamin K deficiency or on warfarin therapy
Overall survival after olt
Post Transplant Surveillance
Imaging every 3-6 months for 2 years, then annually
AFP if initially elevated-then q3mo for 2 years then q6mo
Indications
Milan Criteria
Expanded Milan Criteria (UCSF)
Upto 7 Criteria
MELD Scoring and T staging
Criteria for down staging
LT versus LDT
Pre transplant Evaluation
Procedure
Follow up
Indications: The Milan Criteria
1996, Italy, 48 patients, Mazzafero et al
Single lesion less than 5 cm
Less than 3 lesions none exceeding 3cm
No extrahepatic involvement
No vascular invasion
overall and recurrence-free survivals were 85% and 92%
overall recurrence rate was 8% at 4 years’ follow-up
UCSF-Expanded Milan Criteria
2001
Solitary tumor < 6.5 cm,
or < 3 nodules with the largest lesion < 4.5 cm
and total tumor diameter < 8 cm
Schwartz, Liver Transplantation for Hepatocellular Carcinoma, Gastroenterology. 2004: 127 S268-276.
Vascular invasion
Mc Gill Protocol
Tumors exceeding Milan criteria
Receive 3 TACE treatments at 6 week intervals
Lipiodol,carboplatinum, gelfoam
If patients respond (AFP decreases or tumors shrink, then go on to LT, otherwise continue care)
Upto 7 criteria
HCC with 7 as the sum of the largest tumor (cm) and the number of tumors
Downstaging
LT versus LDT
LDT includes
TACE
RFA
PEI
The published observational studies to date suggest survival following OLT is at least as good as following resection in patients with adequate hepatic reserve.
Liver resection can leave residual liver which is of insufficient size to provide adequate function and as stated before, has the possibility of developing further lesions.
In patients with well-compensated cirrhosis (Child Pugh A) and HCC, the decision whether to resect or transplant remains controversial. However, in the current realm of organ shortage and long waiting times, the decision to resect in this group appears attractive.
If tumor recurrence were to recur than salvage transplantation can be performed.
An observational series has shown primary OLT to have lower operative mortality, recurrence rates and survival rates
Requirements for listing
UNOS provides a set of specific requirements for listing patients with HCC:
(1)Rough evaluation of the number and size of tumors and to rule out extra-hepatic spread by ultrasound, computed tomography (CT) or magnetic resonance imaging (MRI) plus CT of the chest;
(2) Prelisting biopsy is not mandatory, however patients must have one of the following:
(a) a biopsy confirming HCC;
(b) a vascular blush corresponding to the area of suspected HCC;
(c) an α fetoprotein (AFP) > 200 mg/mL;
(d) an arteriogram confirming a tumor;
(e) a history of local ablative therapy(TACE, RFA, PEI);
(3) Patients with chronic liver disease and a rising AFP > 500 mg/dL can also be listed even in the absence of discrete tumor on imaging studies;
(4) The patient must not be a resection candidate;
(5) Reimaging by CT or MRI every 3 mo is required to ensure continued eligibility for OLT.
Bridging therapy
The “dropout” due to tumor progression whilst waiting for OLT is reported to be at least 20%
This problem has furthered the use of local-regional adjuvant therapy (LDT) whilst awaiting transplantation such as TACE, RFA, and PEI.
The ultimate aim of LDT is to provide complete tumor necrosis in an attempt to halt tumor progression.
Analyses of explant specimens subjected to RFA and TACE have shown complete tumor necrosis rates of 47%-66% and 16%-27%, respectively
A retrospective study looking at tumor necrosis in 61 patients did not find any particular modality of LDT to be superior.
Prognostic Factors
Conforming to the “Milan criteria”, in terms of tumor size and tumor burden, gives rise to 3-4-year recurrence free survival rates of up to 92%
Multivariate analysis has shown these to be the only independent variables predicting patient survival and tumor recurrence. Other biological factors such as tumor grading, microvascular invasion and microsatellites appear to play a role, but within the constraints of the size and number burden.
The histological grade of the tumor can be assessed by lesional biopsy and several authors have recommended this approach. Lesional biopsy does however carry the risk of tumor seeding which has been estimated at approximately 2%
Furthermore, significant histological heterogeneity has been described in large tumors, which limits the utility of needle biopsy
Live donor LT
Living donor liver transplantation (LDLT) has evolved over the past decade, mainly in response to the scarcity of donor livers. Deceased liver donation is particularly scarce in Asia, where organ donation rates are less than 5 donors per million population compared to 10-35 per million in Western countries.
LDLT, in particular right liver transplantation, has dramatically increased the number of potential donors. This can eliminate the problem of long waiting times and ‘dropout’ whilst waiting for an organ because of disease progression.
Furthermore, as there is no direct ‘competition’ from other potential transplant recipients the restrictive criteria on tumor burden can be relaxed somewhat.
Survival rates-same as OLT
Recurrence rates-higher
No consensus guidelines for indications
LDLT carries a risk to the donor during hepatectomy with morbidity and mortality rates of 14%-21% and 0.25%-1%, respectively
Using a scoring system including the measurement of “protein induced by vitamin K absence or antagonist-Ⅱ” (PIVKA-Ⅱ), a Japanese group have achieved a 5-year recurrence rate of only 4.9%. PIVKA-Ⅱ, also known as des-carboxyprothrombin, is an abnormal prothrombin protein found in the serum of patients with HCC and in patients with vitamin K deficiency or on warfarin therapy
Overall survival after olt
Post Transplant Surveillance
Imaging every 3-6 months for 2 years, then annually
AFP if initially elevated-then q3mo for 2 years then q6mo
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