Liver Transplantation for  Hepatocellular Carcinoma: History
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Hepatocellular carcinoma (HCC) is the most common primary liver cancer and a leading cause of cancer-related death worldwide.

  • transplant oncology
  • liver transplant
  • gastrointestinal malignancies

1. Liver Transplant Criteria in HCC

LT offers the best chance for optimal long-term outcomes with 5-year post-LT survival of approximately 65–80% and a lifetime recurrence risk of 8–15% [1]. LT is limited by the scarcity of organs, making patient selection crucial. The Milan criteria were published in 1996 and laid the foundation for HCC LT patient selection. Patients with HCC and either a solitary lesion ≤ 5 cm or up to three lesions with each being ≤3 cm without vascular invasion or extra-hepatic involvement are candidates for LT [2]. Due to the success of LT among patients with HCC who met the Milan criteria, transplant surgeons and oncologists have worked to expand the eligibility criteria. The University of California San Francisco [UCSF] criteria recommend LT for patients with a single tumor ≤ 6.5 cm, three tumors with each being ≤4.5 cm with total tumor diameters ≤ 8 cm, or the “up to 7 criteria” where the sum of the maximum tumor diameter and number of tumors must be ≤7 cm. Similarly to the Milan criteria, the exclusion criteria for the UCSF criteria include the presence of major vascular invasion or extra-hepatic disease [3][4]. Post-transplant survival at 5 years was 80.9% and 71.2% for the UCSF and “up to 7 criteria”, respectively.
Additional studies have continued to expand the LT criteria of eligible patients. Toso et al. applied total tumor volume (TTV) < 115 cm3 and alpha-fetoprotein (AFP) levels < 400 ng/mL as criteria for LT among patients with HCC. The authors demonstrated recurrence-free survival and post-transplant survival at 4 years of 68% and 74.6%, respectively [5]. The Kyoto criteria incorporated the HCC tumor marker des-γ-carboxy prothrombin (DCP) < 400 AU/mL, an abnormal variant of prothrombin, and ≤10 tumors, each <5 cm, as the criteria for LT. The authors reported 5-year overall survival (OS) of 82% and a recurrence incidence of 7% [6]. Shimamura et al. proposed the “5-5-500” criteria based on a retrospective review of 965 living donor liver transplantations [LDLTs] among patients with <5 lesions, each <5 cm, and an AFP < 500 ng/mL, of which 301 [31%] were beyond the Milan criteria; the 5-year recurrence rate was 7.3% [7]. The transplant group from Toronto proposed even broader criteria, in which patients with any number or size of tumors were potentially eligible for LT as long as there was no vascular invasion, extrahepatic disease, or poor tumor differentiation. 210 patients were included who underwent transplantation for HCC from 2008 to 2012 and 105 [50%] were beyond the Milan criteria. The researchers reported 5-year survival comparable to patients treated within the Milan criteria (69% for beyond Milan criteria and 78% for those within Milan criteria) [8]. Table 1 summarizes the selection criteria for LT for HCC.
Table 1. Criteria for liver transplant in patients with hepatocellular carcinoma.
Criteria Year Published Definition
Milan Criteria 1996 Single tumor < 5 or 3 tumors < 3 cm.
University of California, San Francisco, Criteria 2001 Single tumor < 6.5 cm or 3 tumors < 4.5 cm, with total diameter of tumors < 8 cm.
Total Tumor Volume Criteria 2008 Total tumor volume < 115 cm3 and serum AFP < 400 ng/mL.
Up to 7 Criteria 2009 Total diameter of all tumors < 7 cm and number of tumors < 7.
Kyoto Criteria 2013 Number of tumors < 10, largest tumor < 5 cm, and DCP < 400 mAU/mL.
Toronto Criteria 2016 No size or number of tumor cut off. Must not have vascular invasion, extrahepatic disease, or poor differentiation.
5-5-500 Rule 2019 Size of tumor < 5 cm, number of tumors < 5, and AFP < 500 ng/mL.
Abbreviations: AFP: alpha-fetoprotein; DCP: des-gamma-carboxyprothrombin.

2. Downstaging HCC for LT

Locoregional therapies such as ablation, transarterial chemoembolization (TACE), and stereotactic body radiation therapy (SBRT) are employed to downstage patients in an attempt to make patients candidates for definitive surgical therapy (resection or transplant). In a phase IIb/III trial, 45 patients were downstaged within the Milan criteria using locoregional or systemic therapy [9]. Patients who underwent LT (n = 23) had 5-year OS of 77.5% versus 31.2% among patients who did not undergo LT. Locoregional therapies resulted in a complete pathologic response in the explanted liver in 23% of patients, which was associated with improved OS and disease-free survival (DFS) [10]. Conversely, patients with a poor response to locoregional therapies upon final pathology were at high risk of post-transplant recurrence [11] Response to treatment can be evaluated through imaging and tumor markers (e.g., AFP or gamma glutamyl transpeptidase) [12] Other studies have also demonstrated that a reduction in AFP to <500 ng/mL was associated with a decreased risk of HCC recurrence and improved post-transplant mortality [13].

3. Organ Availability

The finite donor pool is a rate-limiting step in transplant oncology. While the data are controversial, one way to expand the donor pool is through LDLT. The initial studies raised concerns regarding an increased risk of recurrence of HCC after LDLT; however, more recent studies have demonstrated improved 5-year OS in LDLT versus individuals who had a deceased donor [14][15][16]. The reason for this may be because patients spend less time on the wait list and are less decompensated prior to transplantation. However, LDLT should be limited to high-volume centers to minimize the risk to the donor [17]. Other options to expand the donor pool include the use of “marginal grafts” from older donors, donors after cardiac death (DCD), split livers, and hepatitis-C-infected grafts [18][19][20][21].

4. Future Directions for LT in HCC

Preventing HCC recurrence in the setting of chronic immunosuppression will be crucial to maximize the longevity of transplanted livers. Certain immunosuppression medications, such as calcineurin inhibitors, have been associated with an increased risk of HCC recurrence [22][23]. The SiLVER trial (NCT00355862) assessed the effect of sirolimus, a mammalian target of rapamycin (mTOR) inhibition, on HCC recurrence after LT. Sirolimus use for >3 months was independently associated with reduced mortality, demonstrated a benefit in OS and DFS, and decreased recurrence among patients with elevated AFP (>10 ng/mL) [24].
Equally important in the future of LT for HCC is the identification of predictors of recurrence. Established pathologic characteristics such as T-stage and histologic grade, as well as microvascular invasion and tumor markers such as AFP, have been associated with a risk of recurrence; there is also a growing body of literature regarding the use of fluorodeoxyglucose (FDG) PET/CT to predict the recurrence of HCC after LT [25][26][27][28][29][30][31]. In turn, the use of FDG PET/CT may play a role in the future for patient selection for LT. Overall, LT for HCC is a viable option with favorable outcomes for selected patients who fall within the certain criteria.

This entry is adapted from the peer-reviewed paper 10.3390/medicina59071290


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