Transplanting Children with Hepatocellular Carcinoma How Do They Differ From Adults

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Transplanting Children with Hepatocellular
Carcinoma How Do They Differ From Adults?

• International Liver Transplantation Society
  Eleventh Annual Congress
• Los Angeles, California
• July 22, 2005

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Liver transplantation for HCC in children
Results of Transplantation For HCC 1-
UNOS 2- SIOPEL 3- World review
3

• Hepatic tumors account for approximately 0.5-1.5
  of childhood malignancies, with hepatoblastoma
  and hepatocellular carcinoma constituting the
  majority.
• HCC is less common than HB and is more often
  encountered in children (10-14 years of age).
• HCC often develops in the presence of underlying
  liver disease (hepatitis B, tyrosinaemia).
• The optimal treatment of HCC in children is
  limited given the relative rarity of this tumor,
  and small numbered series reported.
• Compared to HBL, prognosis with HCC is poor
  (10-20 long term survival)

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Pediatric v. Adult HCC

• Same or different entities remains to be
  determined.
• Histology is similar, however, the fibro-lamellar
  variant does not seem to have the better
  prognosis in children as seen in other ages.
• HBL to HCC transition tumor described in
  children.
• Response to chemotherapy is better in children
  than in adults.

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Pediatric v. Adult HCC

• Most pediatric HCC are de novo cases usually
  with no underlying liver disease, in contrast to
  the adult experience where 70-90 of patients
  have cirrhosis (lt40 of children have underlying
  liver disease).
• This may be different in hyperendemic areas for
  HBv.

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Therapeutic Premises of HCC

• Complete tumor excision is the cornerstone of
  successful therapy (feasible in 20 to 40).
• Resectability is limited by multifocality,
  vascular invasion, functional reserve of the
  liver.
• When complete tumor excision is achieved survival
  is better in children (50) than in adults (30 to
  40).

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Therapeutic Premises of HCC

• Total hepatectomy with OLT addresses the cancer
  and the underlying liver disease ( treatable is
  unknown).
• Early experience with OLT and HCC were poor due
  to bulky tumor and early recurrence.
• The finding that incidental HCC had a lower
  reccurrence rate has had a significant impact on
  treatment strategy.

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Liver Allocation for HCC

• Guidelines include no extra-hepatic mets, no
  macro vascular invasion, single tumor not gt 5cm,
  or tumor 3 or lt in and 3cm or lt in diameter
  (Milan criteria).
• UCSF expanded criteria solitary tumor to
  6.5cm, or 3 and 4.5cm (total 8 cm of the
  nodules).
• Allocation for HCC in children presently follows
  adult guidelines. This is applicable in less
  than 50 of children with HCC.

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Chemotherapy and Other Modalities

• Goal is to control or decrease tumor size (in
  potentially resectability), or for palliation.
• Response seen in 40 to 50 of children, which,
  though limited, is better than in adults.
• Role of chemo-embolization, ethanol injection,
  RFA is the same as in adults.

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Outcomes of therapy for HCC

• Uniformly poor in most series (20 to 50), but
  better than in adults (10 to 20).
• This is due to advanced stage of disease at time
  of diagnosis with big/multifocal tumors,
  metastasis, and limited ressectability.

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Pediatric v. Adult HCCTransplantation

• Transplantation for HCC in children is still
  being debated for the de-novo tumors. The
  advanced stage of disease seen in these children
  has resulted in a high recurrence rate.
• Transplantation for HCC in adults is routine,
  though criteria for exception points is strict.

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Patient Count by Primary Diagnosis
(Table 2.1 from 9/20/01 Report)
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Kaplan-Meier Survival from Time of Waitlisting
(1995-1999)
Survival with or without a Transplant
100
All Other Diagnoses
75
MN Other
MN HBL
50
MN HCC
25
0
0 10 20 30
40 50 60
Months Since Waitlisting
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Survival Probabilities and 95 CI for Selected
Diagnoses, 1987-99
(excerpt Table 2.2 from 9/20/01 Report)
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Post-transplant Survival Curves by Diagnosis,
1987-99
Post-transplant Survival
Biliary Atresia
Metabolic Disease
Chol. Liv. Dis/Cirr.
Non-Chol. Cirr.
Other
MN HBL
AHN
MN Other
MN HC
(Figure 2.1 from 9/20/01 Report)
Years Since Transplant
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Summary

• Survival is highest for patients without MN
• Patients with HCC have a survival similar to
  patients without MN until 2 years after listing
• Patients with HBL have a survival similar to
  patients without MN until 4 years after listing
• None of the differences are statistically
  significant

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Summary Post-transplant Survival by Diagnosis
Group, 1987-99

• Confidence intervals for the MN diagnoses are
  relatively wide, due to the small number of
  patients with these diagnoses
• Diagnoses divide roughly into three main groups
• Group 1 (metabolic, cholestatic/cirrhosis,
  non-cholestatic and biliary atresia)
• Group 2 (MNHBL, AHN and Other/Missing)
• Group 3 (MNHC and MNOther)

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Summary Post-transplant Survival by Diagnosis
Group, 1987-99

• At 1 month
• survival probability is significantly higher for
  MNHC and MNOther than for biliary atresia, AHN
  or Other/Missing
• Survival probability for MNHC and MNOther drops
  off drastically during the 2 years after
  transplant
• At 2 and 5 years
• Group 1 has the best survival, and is
  statistically different than MNHC and MNOther,
  which has the lowest survival
• Group 2 diagnoses fall between and are not
  significantly different from the other groups

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Survival Probabilities and 95 CI for Selected
Diagnoses, 1995-99
(excerpt Table 2.3 from 9/20/01 Report)
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Post-transplant Survival Curves by Diagnosis,
1995-99
Post-transplant Survival
Non-Chol. Cirr.
MN HBL
Biliary Atresia
Chol. Liv. Dis/Cirr.
Metabolic Disease
MN HC
Other
AHN
MN Other
(Figure 2.2 from 9/20/01 Report)
Years Since Transplant
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Summary Post-transplant Survival by Diagnosis
Group, 1995-99

• Number of patients with each diagnosis is even
  smaller, and patterns are harder to detect.
• Survival probability for MNHC and MNOther drops
  off drastically in the first 18 months after
  transplant.
• At year 2
• MNOther has statistically worse survival than
  non-cholestatic, metabolic, and biliary atresia
• Biliary atresia is statistically better than AHN
  and Other/Missing

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Summary Post-transplant Survival by Diagnosis
Group, 1995-99

• At year 5
• non-cholestatic, metabolic, and biliary atresia
  are statistically better than AHN and
  Other/Missing
• there is not enough data to assess the MN
  diagnoses at this time.

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Request 2 Study Question(Request 3 from the
9/20/01 Report)

• Compare waiting list mortality risk for pediatric
  liver candidates with and without hepatic tumors
  splitting malignant neoplasms into 3 groups
• Hepatoblastoma
• Hepatocellular Carcinoma
• Other

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Patient Count by Primary Diagnosis
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Waiting List Survival Probability by Primary
Diagnosis
(Table 3.1 from 9/20/01 Report)
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Waiting List Survival Curves by Diagnosis,
1995-99
Waiting List Survival
All Other Diagnoses
MN Other
MN HBL
MN HC
(Figure 3.1 from 9/20/01 Report)
Months Since Wait Listing
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Summary

• Waiting list survival experience for the
  malignant neoplasm diagnoses is lower after 1
  year, compared to all other diagnoses.
• Because of small numbers in the malignant
  neoplasm diagnoses groups, the differences are
  not statistically significant.

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Hepatocellullar Carcinoma (n21)

• Stages I-1, II-4, IVA-10, IVB3
• Associated liver disease 14/21
• Tyrosinemia 4
• Familiar cholestasis 3
• Hepatitis B 3
• Autoimmune hepatitis 2
• Neiman Pick Type C 1
• Wilsons disease 1
• University of Pittsburgh (964 pediatric
  transplants between 1981-2003)

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Treatment Regimen

• Pre-transplant systemic chemotherapy
• Pre-transplant intra-arterial chemotherapy
• Total Hepatectomy
• Unresectable tumor
• Multi-focal disease
• Bilobar disease
• Centrally located disease
• Previous resection with persistent or recurrent
  disease

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Survival Hepatocellular Carcinoma 21 patients

• Alive and disease free 13 patients
• (1, 3, 5 year survival 86, 76, 67 respectively)
• Died with tumor 6
• Died free of tumor 3 pts. (neurologic
  complications of original disease n1, PTLD n1,
  sepsis n1)
• Disease free survival by stages
• Stage I (n1) 100 Stage IVA (n10) 60
• Stage II (n4) 100 Stage IVB (n3) 33
• Stage III (n3) 100
• Medial time to tumor death was 19.5 mos (range 6
  to 58 mos)
• Intra-arterial chemotherapy was effective in 3/5
  pts.

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Factors Influencing Tumor Recurrence in Pediatric
HCC

• Major vascular invasion
• Lymph node involvement
• Tumor size
• Gender (male)

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Conclusion

• Liver transplantation for unresectable HCC can be
  curative.
• Risk factors for recurrence were significant for
  HCC and followed the factors found in the adult
  HCC/transplant population except for number of
  lesions.
• These findings raise the speculation regarding
  the impact of pre-transplant chemotherapy and
  resection of clinical down staging and
  post-transplant survival.

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Liver transplantation for HCC in children

• WHEN ?
• - patient selection
• - contra-indications
• HOW ?
• - timing
• - techniques
• - chemotherapy

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QUESTIONS

• Patient selection
• Pre post-transplant therapy
• Down-staging of tumors
• Medical urgency/priority
• Segmental transplantation
• with/without preservation of IVC

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Is there a fundamental disconnection in the
field?
Benign liver tumour Haemangioendothelioma