Journal List > J Korean Soc Transplant > v.24(1) > 1034327

Lee and Suh: Liver Transplantation for Advanced Hepatocellular Carcinoma

Abstract

Hepatocellular carcinoma (HCC) has become an important indication for liver transplantation in Korea. Even though the Milan criteria have been accepted as the gold standard in deceased donor liver transplantation, the acceptable indication for living donor liver transplantation is controversial. This review covers several key issues in liver transplantation for advanced HCC: (1) recent developments and published data on expanded criteria, (2) the role of downstaging, (3) an ethical issue in expanding the criteria in living donor liver transplantation, and (4) post-operative management, including the immunosuppressive regimen and post-transplant adjuvant chemotherapy to improve survival after transplantation for advanced HCC. Biological factors, such as AFP, PIVKA-II, and a PET scan, in addition to tumor size and number, may be helpful in selecting eligible patients for liver transplantation among patients with advanced HCC. Low-level immunosuppression with low exposure of calcineurin inhibitor may reduce HCC recurrence after transplantation.

References

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Fig. 1.
The HCC ‘Metro Ticket' – the further the distance, the higher the price. Abbreviations: HCC, hepatocellular carcinoma; UCSF, University of California San Francisco. Reprinted from Fig. 1 of reference [5].
jkstn-24-4f1.tif
Fig. 2.
Proposed extended criteria in Asia to show comparable outcome to the Milan criteria. Abbreviations: AMC, Asan Medical Center; SMC, Samsung Medical Center; SNU, Seoul National University; UCSF, University of California San Francisco.
jkstn-24-4f2.tif
Fig. 3.
Kaplan-Meier survival analysis according to 18F-FDG PET findings. Patients with TSUVmax/LSUVmax less than 1.15 showed significantly better survival than those with TSUVmax/LSUVmax of 1.15 or more (P<0.001). Abbreviations: 18F-FDG PET, 18 fluorodeoxyglucose positron emission tomography; LSUVmax, normal liver standard uptake value max; TSUVmax, tumor standard uptake value max. Reprinted from Fig. 4 of reference [20].
jkstn-24-4f3.tif
Fig. 4.
Reported activities of calcineurin inhibitors related to cancer and transplantation. Predicted effect in the presence of calcineurin inhibitors (circled arrows). Abbreviations: EBV, Epstein-Barr virus; IL-6, interleukin 6; MDR, multidrug resistance; TGF-ß, transforming growth factor; VEGF, vascular endothelial growth factor. Reprinted from Fig. 1 of reference [34].
jkstn-24-4f4.tif
Fig. 5.
Reported activities of rapamycin related to cancer and transplantation. Predicted effect in the presence of rapamycin (circled arrows). Abbreviations: IL-6, interleukin 6; mTOR, mammalian target of rapamycin; PTEN, phosphatase and tension homologue deleted on chromosome 10; VEGF, vascular endothelial growth factor. Reprinted from Fig. 2 of reference [34].
jkstn-24-4f5.tif
Table 1.
Expanded criteria in Asian centers
  Radiologic vs Pathologic s Size (cm) and Number Biological factor Additional condition
Milan (2) Radiologic 1 lesion ≤5 cm, or 2 to 3 lesions each ≤3 cm    
UCSF (6) Pathologic 1 lesion ≤6.5 cm, 2–3 lesions each ≤4.5 cm with total tumor diameter ≤8 cm    
Up-to-seven (7) pathologic Seven as the sum of the size of the largest tumor and the number of tumors   Without microscopic invasion
Tokyo 5–5 (8) Radiologic 5 nodules with a maximum diameter of 5 cm    
Seoul National University (18) Radiologic 10 tumors all 5 cm in diameter PIVKA-II 400 mAU/mL  
Asan Medical Center (9) Pathology Largest tumor diameter 5 cm, tumor number ≤6    
Samsung Medical Center (13) Pathologic Any number each ≤5 cm AFP ≤400 ng/mL  
Hangzhou (10) Pathologic (a) Total tumor diameter less than or equal to 8 cm (b) total tumor diameter more than 8 cm, with histopathologic grade I or II and preoperative    
    AFP ≤400 ng/mL, simultaneously    
Kyoto (14) Radiologic 10 tumors, all 5 cm in diameter PIVKA-II ≤400 mAU/m L
Kyushu (15) Pathologic Any number each ≤5 cm DCP ≤300 ng/mL  

Abbreviations: AFP, alpha-fetoprotein; DCP, des-gamma-carboxy prothrombin; PIVKA-II, protein induced by vitamin K absence or antagonist II; UCSF, University of California San Francisco.

Table 2.
Reports on mTOR inhibitors to reduce HCC recurrence after liver transplantation for hepatocellular carcinoma
  Study design Group Survival benefit Side effect
Toso et al. 2007 (40) Retrospective Sirolimus+ FK or CysA+ steroids, n=70 Yes Increased
Zimmerman et al 2008 (41) Retrospective Calcineurine (FK or CysA+ MMF+ steroid, n=52) Sirolimus (FK or CysA+ Sirolimus+ steroid, n=45) Yes No difference
Chinnakotla et al. 2009 (42) Retrospective case-control Control (FK+ MMF, n=106) Sirolimus (Cyclosporine+ Sirolimus, n=121) Yes Tolerable
Vivarelli et al. 2010 (43) Matched-cohort study Control (FK+ steroids, n=31) Sirolimus (FK+ Sirolimus+ steroids, n=31) Yes Tolerable (dyslipidemia 30∼40% in Sirolimus group)

Abbreviations: HCC, hepatocellular carcinoma; MMF, mycophenolate mofetil; mTOR, mammalian target of rapamycin; CysA, cyclosporia A; FK, facrolimus.

Table 3.
Summary of direct effect of immunosuppressants on cancer
  Effect on cancer Side effects
Steroids Neutral (+−) or Slightly pro-tumor (+)
Calcineurin inhibitors Pro-tumor (++) ++
MMF Anti-tumor (−) or no effect (+−)
Sirolimus Anti-tumor (−−) +++

Abbreviation: MMF, mycophenolate mofetil.

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