Liver Transplantation for Advanced Hepatocellular Carcinoma

Kwang-Woong Lee; Kyung-Suk Suh

doi:10.4285/jkstn.2010.24.1.4

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Lee and Suh: Liver Transplantation for Advanced Hepatocellular Carcinoma

Review Article

J Korean Soc Transplant 2010;24(1):4-12.

Published online: 10 March 2010

DOI: https://doi.org/10.4285/jkstn.2010.24.1.4

Liver Transplantation for Advanced Hepatocellular Carcinoma

Kwang-Woong Lee, M.D.¹, Kyung-Suk Suh, M.D.²

¹Center for Liver Cancer, National Cancer Center, Seoul, Korea

²Goyang, Department of Surgery, Seoul National University, College of Medicine, Seoul, Korea

책임저자：서경석, 서울시 종로구 대학로 101서울대학교병원 외과, 110-744 Tel: 02-2072-3789, Fax: 02-766-3975 E-mail: kssuh@snu.ac.kr

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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.

Keywords: Advanced hepatocellular carcinoma, Expanded criteria, Immunosuppressive regimen, Liver transplantation

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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].

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.

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].

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].

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].

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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